Biomedical subjects

D Fosstvedt

Publications and source records attributed to D Fosstvedt.

7 recordsLinked to original sources

PubMed1992

Cimetidine on-demand in dyspepsia. Experience with randomized controlled single-subject trials.

Double-blind randomized controlled trials in single subjects (N of 1 RCTs) have demonstrated a beneficial symptomatic effect of cimetidine in reflux- or ulcer-like non-ulcer dyspepsia (NUD). However, spontaneous fluctuations in symptoms reduce the validity of such trials when performed as continuous trials with fixed dosages. This study was carried out to identify individual responders to cimetidine in NUD, peptic ulcer disease, and oesophagitis and to confirm the beneficial average effect of cimetidine in these clinical entities. We evaluated N of 1 multi-crossover trial designs, which compare the effects of single doses of cimetidine and placebo taken on-demand for symptomatic relief. Each trial consisted of six cimetidine (400 mg or 800 mg) and six placebo tablets randomized in successive pairs. The symptomatic effect of each tablet was measured 1/2-6 h after the intake. Outcomes were assessed by individual p values and confidence intervals. A minimal clinically important difference was defined, to assess the clinical significance as demonstrated by the confidence intervals. Thirteen of 25 patients (52%) with reflux- and ulcer-like NUD obtained individual p values below 0.20. Similarly, 7 of 9 patients (78%) with oesophagitis and 6 of 12 patients (50%) with peptic ulcer obtained such p values. On the basis of the 80% confidence intervals the corresponding numbers of subjects with clinically significant effect were six (NUD), three, and three. The combined data showed a significantly better effect of cimetidine than of placebo (p less than 0.0001) in each of the three diagnostic groups studied. Cimetidine taken on-demand may have a rapid symptom-relieving effect in dyspepsia.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1991

Statistical power in single subject trials.

A controlled single subject trial compares the efficacy of a new treatment with a control treatment in an individual patient. The treatments are administered in a double-blind, randomized, multi-crossover sequence of periods. During the trial response measures are obtained from each treatment period and form the basis for the statistical evaluation. Similar to the situation in clinical trials using groups of patients the statistical power is dependent on sample size, variability of responses, magnitude of the differential treatment effect and the level of statistical significance. In addition, the randomization procedure is of importance and power estimations show that a pairwise random allocation of treatment periods is more powerful than an unrestricted randomization. Since a single subject trial is a time consuming approach, the total number of treatment periods, the sample size, is restricted in order to make such trials feasible. Accordingly, less rigorous statistical requirements and power must be accepted. The consequence is an increased risk of both Type I and II errors. However, in comparison with the trial and error approach frequently applied in clinical practice, the controlled single subject trial may improve the certainty of therapeutic decisions in the individual patient.

Clinical Trials as Topic↗

PubMed1991

The symptomatic effect of 1-day treatment periods with cimetidine in dyspepsia. Combined results from randomized, controlled, single-subject trials.

Before endoscopy a double-blind, randomized, controlled, single-subject trial comparing the symptomatic effect of 1-day treatment periods with cimetidine and placebo was conducted in patients with dyspepsia. Results from 339 patients were analysed. The trial lasted 12 days and consisted of 6 treatment days with 400 mg cimetidine three times daily and 6 days with placebo three times daily. The order of the treatments was randomized within six pairs, and a randomization test based on daily measures of global symptoms provided individual p values. Aggregation of the measures from all subjects showed that cimetidine alleviated the symptoms significantly better than placebo in peptic ulcer disease (PUD) (p less than 0.0001), oesophagitis (p less than 0.001), and non-ulcer dyspepsia (NUD) (p less than 0.0001). Twenty-seven per cent of the patients with PUD, 26% of those with oesophagitis, and 12% of the patients with NUD obtained individual p values of less than 0.10 and were defined as responders. The best predictors of the response to cimetidine in NUD were age above 40 years, heartburn or acid regurgitations being the worst symptom, and night pains relieved by food, milk, or antacids. In conclusion, the applied single-subject trial confirmed the overall symptomatic effect of cimetidine in dyspepsia and identified individual responders among patients with NUD with a clinically reasonable profile. The low proportion of responders among patients with PUD or oesophagitis suggests that the model has a low sensitivity for identification of individual responders and that the single-subject trial design in dyspepsia needs further refinement.

Adult↗

PubMed1991

The controlled single subject trial.

Randomized controlled trials in single subjects ('N of 1 RCT') are double-blind, multi crossover trials in which the effects of two or more treatments are compared within one individual. The aim is to provide a controlled assessment of the efficacy of a new drug in a specific patient. Suitable diseases for single subject trials are particularly those which significantly impair the quality of life and in which there are uncertain treatment effects. Appropriate drugs should have a prompt action, a minimum of carry-over effect, and no side-effects. The trial design is determined by the length, number, and order of successive treatment periods, the outcome measures, and the statistical requirements. Each of these elements may be altered and tailored to the clinical entity and drug(s) applied, thus, providing a large potential for design options.

Double-Blind Method↗

PubMed1991

Combined single subject trials.

Randomized controlled single subject trials are designed as multiple crossovers between the treatments to be compared. Results from such independent trials may be combined and integrated for the purpose of extending the conclusions beyond the single subject. Unlike the conventional crossover group trial, the primary goal of the combined single subject study is not to demonstrate an overall clinical benefit of a drug, but to indicate the features typical for drug responders. The external validity of combined single subject trials depends on the same prerequisites as are employed in group trials: strict entry criteria, uniform treatment procedures, consensus targets for outcome measures, and acceptable statistical tests. In clinical research the main role of combined single subject trials should be to elucidate new insight and generate hypotheses that could optimize the design of subsequent group trials.

Data Interpretation, Statistical↗

PubMed1990

Statistical aspects of controlled single subject trials.

Randomized controlled trials in groups and single subjects differ in several statistical aspects. In group trials the experimental unit is a randomly selected subject from a predefined population and this subject is randomly assigned to a treatment. Outcome is confined to average effects which can be generalized to the specific population, but which do not necessarily apply to individual persons. In single subject trials the experimental unit is a treatment period and each treatment period is randomly allocated in a multiple cross-over sequence of periods. The single subject is only representative of itself, but similar responses in corresponding single subject trials may justify careful extrapolation of the results. Single subject trials have a high risk of Type II errors. However, the randomization procedure chosen and the type of statistical test applied may enhance the statistical power of such trials. Internal validity depends on modeling the trial design to the clinical features, drug properties and statistical requirements, while reliability is determined by the reproducibility of the trial response.

Humans↗

PubMed1988

Experience with a multi crossover model in dyspepsia.

A multi cross over model (MCOM) has been designed for single case studies. The model which is only partly randomized, implies regular interchanges between treatment periods with active drug and placebo. The individual evaluation is based on the number of times the active drug is associated with less symptoms than the preceding or following placebo period (X-score), while the effect in a group is evaluated according to the X-score distribution and a paired t-test. The advantages of the single case approach and the impact of the MCOM is illustrated by the results from a study of the effect of cimetidine in non ulcer dyspepsia. Although there are several statistical objections to the model, the results from the study are reasonable and demonstrate a small degree of violence of preassumptions.

Cimetidine↗