To investigate single and combined effects of daily dietary supplementation with 50 mg of vitamin B6 and 200 mg magnesium (as MgO) for one cycle for the relief of mild premenstrual symptoms, a randomized, double-blind, placebo-controlled, crossover design was used. Forty-four women with an average age of 32 years took part in the study. Each woman was randomly assigned, according to a Latin square design, to take consecutively all four of the following treatments daily for one menstrual cycle: (1) 200 mg Mg, (2) 50 mg vitamin B6, (3) 200 mg Mg + 50 mg vitamin B6 and (4) placebo. Throughout the study, each volunteer kept a daily record of symptoms using a 5-point ordinal scale in a menstrual diary of 30 symptoms. Symptoms were grouped into six categories: anxiety, craving, depression, hydration, other, and total. Urinary magnesium output for 24 hours was estimated using the Mg/creatinine concentration ratio. ANOVA showed no overall difference between individual treatments, but predefined treatment comparisons using factorial contrasts in ANOVA showed a significant effect of 200 mg/day Mg + 50 mg/day vitamin B6 on reducing anxiety-related premenstrual symptoms (nervous tension, mood swings, irritability, or anxiety) (p = 0.040). Urinary Mg output was not affected by treatment. A small synergistic effect of a daily dietary supplementation with a combination of Mg + vitamin B6 in the reduction of mild premenstrual anxiety-related symptoms was demonstrated during treatment of 44 women for one menstrual cycle. In view of the modest effect found, further studies are needed before making general recommendations for the treatment of premenstrual symptoms. The study indicated that absorption from MgO was poor and daily supplementation for longer than 1 month is necessary for tissue repletion.

Between 1993 and 1996, a total of 452 patients were entered into a randomized trial evaluating eliprodil (a non-competitive NMDA receptor antagonist) in patients suffering from severe head injury. The primary efficacy analysis concerned the Glasgow Outcome Score (GOS), six months after randomization. This outcome was classified into three ordered categories: good recovery; moderate disability, and the worst category made up by combining severe disability, vegetative state and dead. A sample size calculation was performed prior to the commencement of the study, using a formula which depends on the anticipated proportions of patients in the three different outcome categories, the proportional odds assumption and on the relationship between outcome and prognostic factors such as Glasgow Coma Score at entry. Owing to uncertainty about the influence of prognostic factors, and about the proportion of patients in the three GOS categories, a blinded sample size review was planned. This review was performed on the basis of the first 93 patients to respond, and this led to an increase in the sample size from 400 to 450. In this paper the pre-trial simulations showing that the type I error rate would be influenced and the power would be preserved will be presented, and the implementation of the procedure will be described.

Large clinical trials in life‐threatening conditions are usually conducted under the surveillance of a Data and Safety Monitoring Board (DSMB), whose remit is to protect the ethical and safety interests of the patients. The purpose of this paper is to describe a formal approach to safety monitoring, using a sequential safety procedure to aid the decisions made by the DSMB. This procedure is designed to recommend termination of the study as soon as evidence that the experimental treatment is worse than the control in terms of the primary safety response is so strong that it is unethical to proceed. The use of this formal sequential procedure enables probabilities of the study stopping erroneously and stopping correctly, under various degrees of experimental treatment disadvantage, to be examined. Also scenarios depicting data sets which lead to continuing or stopping can be presented. Such explorations are useful in encouraging all DSMB members to consider carefully, prior to the start of a study, the conditions under which they would seriously wish to consider termination. The implementation of these methods is described for three recently completed trials in which it has been used. Finally, our current recommendations for the design of these procedures, arising from these and other similar experiences, are given. Copyright © 2000 John Wiley & Sons, Ltd.

In a sequential clinical trial, accrual of data on patients often continues after the stopping criterion for the study has been met. This is termed "overrunning." Overrunning occurs mainly when the primary response from each patient is measured after some extended observation period. The objective of this article is to compare two methods of allowing for overrunning. In particular, simulation studies are reported that assess the two procedures in terms of how well they maintain the intended type I error rate. The effect on power resulting from the incorporation of "overrunning data" using the two procedures is evaluated.

The International Citicoline Trial in acUte Stroke is a sequential phase III study of the use of the drug citicoline in the treatment of acute ischaemic stroke, which was initiated in 2006 in 56 treatment centres. The primary objective of the trial is to demonstrate improved recovery of patients randomized to citicoline relative to those randomized to placebo after 12 weeks of follow-up. The primary analysis will take the form of a global test combining the dichotomized results of assessments on three well-established scales: the Barthel Index, the modified Rankin scale and the National Institutes of Health Stroke Scale. This approach was previously used in the analysis of the influential National Institute of Neurological Disorders and Stroke trial of recombinant tissue plasminogen activator in stroke.The purpose of this paper is to describe how this trial was designed, and in particular how the simultaneous objectives of taking into account three assessment scales, performing a series of interim analyses and conducting treatment allocation and adjusting the analyses to account for prognostic factors, including more than 50 treatment centres, were addressed.