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Biomedical subjects

A F Ebbutt

Publications and source records attributed to A F Ebbutt.

8 recordsLinked to original sources
PubMed1997

Simple models for repeated ordinal responses with an application to a seasonal rhinitis clinical trial.

In contrast to other models for ordinal data, the continuation ratio model can be fitted with standard statistical software. This makes it particularly appropriate for large clinical trials with ordinal response variables. In addition, when the trials are longitudinal, this model can be applied to individual responses instead of frequencies in contingency tables. Dependence can be incorporated by conditioning on the previous response, yielding a form of Markov chain. This approach is applied to the analysis of a large seasonal rhinitis trial, where patients were observed over 28 days and six symptoms recorded as ordinal responses.

Humans↗
PubMed1996

Trials to assess equivalence: the importance of rigorous methods.

The aim of an equivalence trial is to show the therapeutic equivalence of two treatments, usually a new drug under development and an existing drug for the same disease used as a standard active comparator. Unfortunately the principles that govern the design, conduct, and analysis of equivalence trials are not as well understood as they should be. Consequently such trials often include too few patients or have intrinsic design biases which tend towards the conclusion of no difference. In addition the application of hypothesis testing in analysing and interpreting data from such trials sometimes compounds the drawing of inappropriate conclusions, and the inclusion and exclusion of patients from analysis may be poorly managed. The design of equivalence trials should mirror that of earlier successful trials of the active comparator as closely as possible. Patient losses and other deviations from the protocol should be minimised; analysis strategies to deal with unavoidable problems should not centre on an "intention to treat" analysis but should seek to show the similarity of results from a range of approaches. Analysis should be based on confidence intervals, and this also carries implications for the estimation of the required numbers of patients at the design stage.

Clinical Trials as Topic↗
PubMed1984

Three-period crossover designs for two treatments.

The use of three periods in the two-treatment crossover design for clinical trials is considered. It is proposed that a series of such trials in a particular therapeutic area may establish the relevance of the crossover design in that area. Treatment sequences to be used in three-period two-treatment trials are discussed. Two possible designs which allow carryover effects to be tested against the within-subject variability are compared. A design involving four treatment sequences is recommended.

Clinical Trials as Topic↗
PubMed1980

Lipids and lipoprotein fractions after cyclopenthiazide and oxprenolol: a double-blind crossover study.

A double-blind crossover study was carried out to investigate the effects of cyclopenthiazide and oxprenolol on blood lipids in 20 previously untreated patients with mild to moderate hypertension. After a 4-week placebo period, patients received at random either 8-weeks' treatment with the two drugs followed by 8 weeks on cyclopenthiazide alone, or the reversed sequence. Daily doses were 160 mg slow-release oxprenolol and/or 0.25 mg cyclopenthiazide during the first 4 weeks of each treatment period, after which the dosage was doubled. Data from 13 patients who completed the trial showed no significant changes in the blood levels of triglycerides, total cholesterol or LDL and HDL cholesterol fractions. These findings are discussed in relation to published studies on the effects of other beta-blockers on blood lipids.

Cholesterol↗
PubMed1979

A multicentre study examining the substitution of Trasidrex for the free combination of Slow-Trasicor and Navidrex-K.

A multicentre, open study of general practice patients with essential hypertension who were currently being treated with oxprenolol and cyclopenthiazide was undertaken in which the patients were transferred to Trasidrex for 12 weeks. Weight, blood pressure, heart rate and side-effects were assessed pre-trial and at 4-week intervals. A global assessment was also made at the same time intervals. The mean serum potassium remained virtually unchanged after 12 weeks treatment with Trasidrex. Blood pressure control was marginally improved during the study and it is thought possible that better patient compliance might explain this. Trasidrex was tolerated equally as well as the free combination.

Antihypertensive Agents↗
PubMed1976

Tofranil in the treatment of low back pain.

This report describes a double-blind between-group comparison of Tofranil and placebo in fifty-nine patients admitted to the Joint Service Medical Rehabilitation Unit suffering from low back pain. Patients were given 25 mg of either Tofranil or placebo three times a day for four weeks. Fifteen patients were not included in the analysis, nine dropping out for non-trial related reasons, two dropping out complaining of lost libido and four not taking the tablets, or taking additional drugs. One of the patients complaining of lost libido was taking Tofranil and the other was taking placebo. Over the whole sample there was no significant benefit for Tofranil over placebo as regards physical measurements. Both Tofranil and placebo groups showed a significant improvement during the trial on straight leg raise and backward flexion. For lateral flexion the Tofranil group was significantly worse than the placebo group on entering the trial, and during the trial the Tofranil group improved to match the placebo group. The clinician's pain and stiffness assessments and the patients' pain and stiffness assessments show a significant improvement for both the Tofranil and placebo groups during the trial. However, no difference is shown between Tofranil and placebo. The psychological tests show no difference between Tofranil and placebo and only a marinal improvenmet over initial condition. Further analysis according to initial diagnosis showed nothing conclusive. Numerically, the use of Tofranil produced a marked improvement in pain and stiffness in patients with 'disc lesion only' diagnoses, whereas placebo did not produce an improvement. However, this observation was far from reaching statistical significance. Side-effects were not severe for either drug. Additional medication was rarely used.

Adolescent↗
PubMedDate not supplied

Practical issues in equivalence trials.

Equivalence trials aim to show that two treatments have equivalent therapeutic effects. The approach is to define, in advance, a range of equivalence -d to +d for the treatment difference such that any value in the range is clinically unimportant. If the confidence interval for the difference, calculated after the trial, lies entirely within the interval, then equivalence is claimed. Glaxo Wellcome has carried out a series of trials using this methodology to assess new formulations of inhaled beta-agonists and inhaled steroids in asthma. Eleven of these trials are used to review some practical issues in equivalence trials. For the series of asthma trials, a range for peak expiratory flow rate (PEF) from -15 to +15 l/min was chosen to be the range of equivalence. This fitted well with physicians' opinions and with previously demonstrated differences between active and placebo. The choice of the size of the confidence interval should depend on the medical severity of the clinical endpoints under consideration and the level of risk acceptable in assuming equivalence if a difference of potential importance exists. From this point of view, a recommendation in the CPMP Note for Guidance on Biostatistics that 95 per cent confidence intervals should be used is inappropriate. Intent-to-treat (ITT) and per-protocol (PP) analyses were compared for the eleven asthma trials. Confidence intervals were always wider for the PP analysis and this was entirely due to the smaller number of subjects included in the PP analysis. There was no evidence that the ITT analyses were more conservative in their estimates of treatment difference. The need to demonstrate equivalence in both an ITT and a PP analysis in a regulatory trial increases the regulatory burden on drug developers. The relative importance of the two analyses will depend on the definitions used in particular therapeutic areas. Demonstrating equivalence in one population with strong support from the other would be preferred from the Industry viewpoint. In trials with regulatory importance, prior agreement with regulators on the role of ITT and PP populations should be sought. Trial designs will need to take account of the estimated size of the PP population if adequate power is needed for both analyses. Careful design in the series of asthma trials, particularly identifying a population of patients with potential to improve, resulted in notable increases in lung function during the course of the trials for both treatments. This provided reassurance that equivalence was not due to a lack of efficacy for both treatments. In one trial equivalence was demonstrated overall but a treatment by country interaction was noted. However, this interaction could not be attributed to differences in patient characteristics or baseline data between the countries. Study conduct was also similar in the different countries. The conclusion was that the interaction was spurious and that the trial provided good evidence of equivalence.

Adult↗