The limitations of this design include the fact double-blinding is only really present in the first trial period, since with this design in the second period all the patients receive active treatment. In addition, the evolution of the symptoms during the follow-up can enable the treatment group type 2 diabetes for the previous period to be identified. This can induce an evaluation bias. A carry-over effect from the first to the second period cannot be excluded, as well as a training effect if the primary criterion is a score. Hence, this type of trial is almost always explicative (i.e. evaluates the effect of the treatment on the symptoms and the evolution of the disease), losing all its pragmatic repercussions, unlike, for example, a classical parallel group trial with a follow-up equivalent to the two periods in the delayed start design.

Minimising time on inactive treatment or placebo: randomised withdrawal, early escape, randomised placebo phase, stepped wedge designs With the randomised withdrawal design, all eligible patients with the disease being studied receive open-label treatment for a specified period to identify a subgroup of patients who can successfully achieve a pre-defined level of response. The patients in this subgroup are then randomized to continue the tested treatment or to receive a placebo in a double-blind fashion. The randomised withdrawal design aims to evaluate the optimal duration of a treatment in patients who respond to the treatment. In the randomised early escape design, for the patients who do not respond to therapy, time on ineffective treatment is minimised.

Both these designs are combined in the three-stage randomised trial design. In the other possible designs (randomised placebo phase, stepped wedge trials) the time spent on placebo is minimised, and all patients receive the active treatment at the end. Adaptive randomisation (play the winner, drop the looser designs) The play-the-winner and the drop-the-loser designs aim to favour the group with the best chance of success by increasing the probability of patients being randomised to that group. For adaptive randomization designs, the procedure is best described by using the urn model which is common in the statistical literature; in the urn there are various types of balls representing particular treatments; patients accrue sequentially and at each stage, the probability of allocating a particular treatment to a given patient depends on the number of various types of balls in the urn.

The response of each patient after treatment plays an essential role in the determination of subsequent compositions of balls in the urn. In the randomized play the winner (PW) procedure, the basic strategy is to ��reward�� more balls to successful Cilengitide treatments. The urn contains K different types of balls, representing K different treatments.