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PubMed1986

Using baseline measurements in the two-period crossover clinical trial.

In a clinical trial designed to compare the efficacy of two treatments, use can be made of the two-period crossover design, in which each patient is randomly assigned to receive both treatments in one of two sequences. A restriction of its utilization involves the issue of carryover effect, otherwise known as sequence effect or treatment by period interaction. Carryover effects can sometimes be eliminated by using baseline measurements taken at the beginning of each period just prior to treatment. We examine this approach of using baseline measurements in this setting and find that there are many circumstances in which, in spite of eliminating carryover, the use of baseline measurements provides a less powerful test of treatment effect and a less precise estimate of the treatment difference.

Clinical Trials as Topic↗
PubMed1990

A simple method for the estimation of interaction bias in crossover studies.

The crossover trial is considered the most powerful means of determining the efficacy of new drugs. However this study design is frequently invalidated by treatment-by-period interaction. If, for example, the effect of the first treatment period carries on into the next one, then it influences the response to the latter period (carryover effect). A second problem is that there are no reliable statistical methods to test for this potential bias. This article takes issue with these problems and gives an alternative method for the detection of interaction simply by looking at the data. In a crossover without interaction the second period should be a true reflection of the first. If, however, the data of a treatment are better in the second period than in the first, a carryover effect is probable. If worse, a rebound phenomenon or a negative carryover effect is likely. If both treatments are better or worse, a time effect or some other external influence might be present. The authors illustrate this simple method by a summary of a few selected trials that have been published recently. This method enables not only the detection of interaction but also the differentiation between different types of interactions. Therefore, investigators are advised to use it in order to make sure that there are no unexpected problems.

Bias↗
PubMed1999

Design and analysis issues for crossover designs in phase I clinical studies.

To assess the efficacy of potential new drugs in the initial phase of clinical research, one must use an efficient design that satisfies conditions to guarantee the safety of the subjects. For a parallel design, a two-period crossover design, two three-period crossover designs, and a Latin square design with three periods, we compared variances of estimators based on a mixed analysis of variance model. The proposed three-period crossover designs turned out to be only slightly less efficient than the Latin square design, which is not capable of satisfying the necessary safety conditions. The analysis of data from the crossover design poses several problems, including nonconstant variances for all observations and the possibility of carryover effects. To resolve these issues, we generalized the Box-Cox transformations to the mixed model at hand and, using simulation, investigated the sensitivity of the analysis to the presence of (first-order) carryover effects. This showed that results from the model without carryover are reliable for only very small carryover effects.

Clinical Trials, Phase I as Topic↗
PubMed2026

Prior exposure to hypoxia alters DNA methylation patterns in the eastern oyster.

Environmentally induced epigenetic changes (e.g., DNA methylation) can alter genetic activity to help organisms adapt and respond to variable environments. While many studies have investigated DNA methylation as a response to a stressor at a single timepoint, less well-understood is how methylation may encode memory of past environments and influence the response to current environments (i.e., carryover effects). Oysters are an excellent natural system to study carryover effects due to their sessile nature, which may expose them to increased environmental variability. To better understand how methylation changes in response to a previous exposure of environmental stress, we conducted a fully factorial experiment exposing juvenile oysters to either control or hypoxic conditions at two timepoints separated by 60 days. After the second exposure, whole body tissue samples were collected and processed for methylRAD sequencing. Regardless of treatment, methylation was mostly found in exons. We found both the first and second exposure treatments contributed significantly to the observed variation in gene body methylation. Interestingly, oysters that were first exposed to hypoxia and later exposed to control conditions had methylation patterns that differed the most from any other condition. We found that differentially methylated genes identified in pairwise comparisons were mainly involved in the oxidative stress response, metabolism, and transcription. Together, these findings suggest that early life environments have a lasting impact on the epigenome and that the timing of stress elicits unique response strategies, which highlights potential targets of resilience for oysters.

Animals↗
PubMed2004

Analysis of two-treatment, two-period crossover trials in emergency medicine.

In an AB/BA crossover trial, patients are randomly assigned to receive either treastment A in the first period followed by treatment B in the second period or treatment B in the first period followed by treatment A in the second period. The crossover trial allows for a within-patient comparison between treatments because each patient serves as his or her own control subject, removes the interpatient variability from the comparison between treatments, and can provide unbiased estimates for the differences between treatments. When applied inappropriately, crossover designs have serious problems that might adversely influence and invalidate their results. The primary concern is the residual carryover effect of a treatment in subsequent treatment periods. Rather than depending on a statistical procedure to eliminate the possibility of the presence of carryover effects, it is more important that the crossover design be used only in those situations in which the likelihood of a carryover effect is exceptionally small. Even though the AB/BA crossover trial appeals to the physician researcher, it is surprisingly difficult to take advantage of this design. The primary objective of this article is to introduce readers and trialists to some of the issues surrounding crossover trials. Researchers who use this design should explicitly examine the assumptions about crossover effects and the adequacy of the lead-in washout period and the between-period washout period and clearly indicate that the results of the study are conditional on the acceptance of those conditions.

Biomedical Research↗
PubMed2002

Phase III evaluation of nortriptyline for alleviation of symptoms of cis-platinum-induced peripheral neuropathy.

Tricyclic antidepressants have been reported to relieve the paresthesiae associated with peripheral neuropathies of many etiologies. We designed a randomized, double-blind, placebo-controlled, crossover trial to establish the efficacy of nortriptyline in the treatment of cis-diamminedichloroplatinum (CDDP)-induced paresthesiae. The study included 51 evaluable patients with CDDP-induced peripheral neuropathy and painful paresthesiae. The study consisted of two 4 week phases, separated by a 1 week 'wash-out' period, in which patients received escalating dosages of either placebo or nortriptyline. The target maximum dose of nortriptyline was 100 mg/day. Each patient filled out pre-randomization and then weekly questionnaires assessing paresthesiae severity, hours of sleep, quality of life, and adverse effects over the 9 week study. No significant differences in paresthesia were observed in the first treatment period between nortriptyline and placebo (means of 49 and 55 respectively on a 0-100 point scale, P=0.78). Although some evidence of a modest effect in favor of nortriptyline was observed during the second treatment period (about one patient in five got a 10-point reduction in pain from drug above placebo effect), this occurred in the presence of a strong carryover effect. Linear models analysis and Bayes methods confirmed that the effect of nortriptyline on paresthesia was modest at best. Hours of sleep increased in the nortriptyline phase (P=0.02). There was no significant difference in measures of quality of life and the effect of paresthesiae on patients' daily activities between nortriptyline and placebo. There was no major toxicity associated with nortriptyline, but dry mouth, dizziness, and constipation were more common with nortriptyline. In summary, nortriptyline failed to demonstrate strong evidence of any effect on paresthesia or pain. The presence of a potential effect which appeared in the second period of the crossover design is questionable due to the observed carryover effect. Cross-validation sensitivity analysis of results support the conclusion that nortriptyline provides modest improvement at best over placebo in terms of chemotherapy-related neuropathy.

Antidepressive Agents, Tricyclic↗
PubMed1999

Effects of standard and high doses of salmeterol on lung function of hospitalized patients with cystic fibrosis.

In a recent investigation we found that hospitalized patients with cystic fibrosis who received 0.5 cc of 0.5% albuterol nebulizer solution TID significantly increased their pulmonary function across the day, but fell back to baseline overnight. To determine whether this fall could be prevented by the long-acting beta-2 agonist salmeterol at both standard (2 puffs: 42 mcg BID) and high (4 puffs, 84 mcg BID) doses, we evaluated the effects of salmeterol vs. albuterol (2 puffs, 180 mcg QID, and 4 puffs, 360 mcg BID) in a placebo-controlled three-way random crossover, double-blind trial. Eighteen patients in the low-dose group and 10 of the same 18 patients in the high-dose group completed the 3 consecutive days of testing and received either salmeterol, albuterol, or placebo with each of four chest physiotherapy sessions given at 7 AM, 11 AM, 3 PM, and 7 PM. At standard doses (2 puffs), the mean percent changes in FEV1 pre- to post-7 AM therapy for salmeterol (5.5%) and albuterol (9.9%) were significantly greater than with placebo (-1.2%) (P < 0.05 and 0.01, respectively). The mean percent changes in FEV1 from morning baseline with salmeterol were also significantly greater than placebo before 3 PM (12.1% vs. 5.4%, P < 0.01), and neither albuterol nor salmeterol were significantly greater than placebo after 3 PM. At standard doses there was a significant carryover effect with salmeterol to the next morning for the FEV1 (7.3%) when compared to placebo (1.5%) and albuterol (-0.7%) (P < 0.05 and 0.05, respectively). At high doses (4 puffs), the mean percent change in FEV1 with pre- to post-7 AM therapy increased to 22.7% and remained significantly greater than with placebo until pretherapy at 7 PM. The carryover effect the next morning was 14.7%. Salmeterol at 4 puffs compared favorably to albuterol nebulizer therapy given TID in both the incidence of responders for the FEV1 (70% vs. 71%) and the mean changes after therapy at 7 AM (22.7% vs. 14.9%), and provided greater carryover effects to the next morning (14.7% vs. -0.7%), thus preventing the fall in pulmonary function back to baseline overnight. We recommend the use of high-dose salmeterol in hospitalized patients with FVC values of 40% of predicted or greater, starting with 2 and increasing to 4 puffs BID as tolerated.

Administration, Inhalation↗
PubMed1989

A two-period crossover design for the comparison of two active treatments and placebo.

This paper discusses a two-period crossover design for the comparison of two active treatments (A and B) and placebo (P) for relief of recurrent symptoms of a chronic health disorder. It is based on blocks of ten patients for which the treatment sequences A:B and B:A are each assigned to three patients and the sequences A:P, P:A, B:P, and P:B are each assigned to one patient; thus, treatment periods have a 2:2:1 allocation for A, B, and P. The principal model for analysis of this design involves additive subject effects, period effects, and treatment effects. Analysis of within-patient differences provides an estimate of the comparison between active treatments with variance (2vw/7r) and an estimate of the comparison between an active treatment and placebo with variance (4vw/7r); here vw is the within-patient variance and r is the number of blocks of ten patients. Analyses which address carryover effects and treatment effects adjusted for carryover effects are also described. An example using simulated data on relief of recurrent gastrointestinal pain illustrates the methodology.

Chronic Disease↗
PubMedDate not supplied

Assessment of the use of sialogogues in the clinical management of patients with xerostomia.

This study was conducted to assess the clinical efficacy and adverse effects of pilocarpine, bethanechol and cevimeline in patients with xerostomia. In this open-label crossover assessment in 20 patients with xerostomia, a one- to two-week course of each medication with a one-week washout period was prescribed. Side effects, symptoms, whole stimulated and unstimulated saliva were measured. Each sialogogue was found to increase saliva and decrease symptoms. A mixed-effects analysis showed a greater increase in stimulated saliva on bethanechol compared to pilocarpine (0.106, p = 0.0272). Increased sweating was the most common side effect, experienced more frequently with pilocarpine as compared to bethanechol (p = 0.0588) or cevimeline (p = 0.0143). A carryover effect beyond the washout period was seen. Effects on saliva and side effects vary between sialogogues, suggesting a benefit of trials with different sialogogues to determine individual patient preference. The observed carryover effect suggests that intermittent treatment may be an alternative to continuous treatment with sialogogues.

Bethanechol↗
PubMed1994

A comparative study of several antibiotic formulations using a design based on a combination of balanced incomplete blocks and Latin squares.

A practical application of an experimental design, suitable for the comparison of several treatments, and based on combining balanced incomplete blocks and Latin squares balanced for carryover effects, is presented in the context of comparing a number of paediatric antibiotic formulations for taste, smell and colour. The recommended designs originally suggested by Patterson, have the advantage of balanced incomplete blocks, in that a single trial may be used to compare a larger number of treatments than may reasonably be given to any individual subject. In addition, the incorporation of suitably chosen Latin squares allows for assessment of any effect of order of presentation of the treatments and for any simple first-order carryover effect of one treatment into the following treatment period. Inclusion of such effects in the overall analysis could result in the reduction of bias in the comparisons of the treatments.

Analysis of Variance↗
PubMed1980

The crossover experiment for clinical trials.

The two-period crossover or changeover design for clinical trials is compared with other simple designs in terms of statistical precision and cost. The sensitivity of the crossover to bias due to carryover effects is examined. The feasibility of using the crossover data to test for the existence of carryover effects is investigated and found to be uneconomical. A numerical example is presented.

Clinical Trials as Topic↗
PubMed1995

A simple analysis of crossover studies with one-group interaction.

The crossover trial has an intuitive appeal to clinicians because each patient is use as his own control. Thus, between-subject variability of symptoms is eliminated. However, this study design suffers frequently from the bias of treatment-by-period interaction. If, for example, the effect of the first treatment period carries on into the next one, then it influences the response to the later period (carryover effect). A second problem is that the standard approach (Hills-Armitage analysis) for interaction has little power. This led the FDA and some statisticians to discourage the use of crossovers. In the present report I take issue with the common clinical situation where there is carryover effect in only one of the groups of a trial and present a simplified analysis for this situation with more power than the standard analysis.

Analysis of Variance↗
PubMed1989

Double-blind crossover versus parallel groups in hypertension.

The efficacy of antihypertensive drugs requires evaluation in clinical trials, the design of which must minimize variability (observer or patient) and order effects, eliminate bias, and include sufficient numbers of patients (i.e., have sufficient power) to allow real differences in blood pressure between patient groups to be detected at conventional levels of statistical significance. The crossover design of trial requires the successive examination of different treatments. This may result in a lengthy trial for the participant and an increase in the dropout rate. Therefore the parallel group design is usually performed for a comparison of several active drugs or drugs and placebo. This design avoids the potential problems of order and carryover effects, and when of a long duration, takes into account short-term and longer term responses to drugs. Crossover trials with limited periods of treatment for each phase can be carried out with fewer numbers of subjects and are more economical of patient resources. However, care must be taken to correct for order effects by appropriate design and to exclude carryover effects. Usually such a design only allows the investigator to comment on short-term blood pressure responses. The extrapolation of such information for longer term use of the drugs in clinical practice requires much caution.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2004

The place of the crossover design in infertility trials: a maximum likelihood approach.

BACKGROUND: For some years, there has been a debate as to the place of the crossover trial in assisted reproduction technology (ART). We aimed to investigate whether crossover and parallel designs result in different estimates of treatment effects. METHODS: We carried out computer simulation of cohorts of patients undergoing either intra-uterine insemination (IUI) or IVF under both parallel and crossover designs, under scenarios involving censoring and carryover effects. Results of the simulation were analysed using a maximum likelihood approach. RESULTS: No relevant difference was found between the designs. The crossover design resulted in slightly more pregnancies than the parallel design. Carryover effects may slightly distort the estimates of treatment effects. Crossover and parallel designs will produce essentially the same statistical estimates of treatment effect and percentage of pregnancies. The crossover design is an acceptable design in infertility research provided the data are analysed correctly.

Clinical Trials as Topic↗
PubMed1992

Crossover trials comparing several treatments.

Designs exist for crossover studies in which the possibility of distortion by carryover effects is minimised. A novel design including 5 treatments and 15 subjects with this property is presented, along with existing designs. These designs incorporating balance for carryover effects should be used in preference to cyclical permutation designs. Statistical analysis of the resulting data is readily performed.

Analysis of Variance↗
PubMedDate not supplied

Contextual variation of the vowel voice source as a function of adjacent consonants.

The contextual effects of voiced/voiceless stops on the voice source of an adjacent vowel were examined for the first vowel in 'CVCV utterances in German, English, Swedish, French, and Italian. The principal analysis technique involved interactive inverse filtering and parameterisation of the glottal waveform in terms of a four-parameter voice source model (the LF-model). This analysis procedure was supplemented by measures from narrow-band spectral sections of the speech output and by oral airflow recordings which allow inferences about the relative timing of glottal and supraglottal gestures. Results indicated that the voiced/voiceless nature of the consonant does yield differences in the voice source of the vowel. The most striking effects were found in the context of voiceless consonants, and cross-language differences did emerge in terms of directionality and degree. Extensive anticipatory effects were found for Swedish and for some speakers of English. Preceding the voiceless stop the vowel becomes increasingly breathy-voiced, and it would appear that the glottal abduction gesture is anticipated very early in the course of the vowel. Italian exhibited a similar tendency, though to a considerably lesser degree. The German data, on the other hand, showed certain strong carryover effects: Following the voiceless aspirated stop there was extensive breathy voicing. French showed little contextual variation in either direction. Rather surprisingly, the observed effects were not directly correlated with, or predictable from, the phonetic categories involved (voiced, voiceless unaspirated, and voiceless postaspirated). These results yield insights into the control parameters which may be involved in regulating voicing oppositions in these languages. Whereas the anticipatory effects observed might be consistent with a "timing" model of glottal control, the carryover effects cannot be explained in terms of timing alone and suggest that differences in tension settings of the laryngeal musculature may also be implicated.

Female↗
PubMed1989

A critique of recent research on the two-treatment crossover design.

A critical review is provided of recent articles on two-treatment crossover trials that purport to provide solutions to the problems caused by the existence of differential carryover effects. Included in the review are papers suggesting that extra-period designs be employed in which treatments follow themselves, that the bias caused by a difference between the carryover effects may sometimes be ignored, that changes from baseline be analyzed, and that a series of preliminary tests using baseline values be performed. The validity of many of these suggestions is shown to depend on whether mathematical assumptions that are generally unverifiable are satisfied. The two-period crossover design is recommended only when prior experience suggests that its assumptions are likely to be satisfied.

Bias↗
PubMed1993

Feasibility of an every-other-night regimen in insomniac patients: subjective hypnotic effectiveness of quazepam, triazolam, and placebo.

BACKGROUND: Rebound insomnia, a worsening of sleep difficulty beyond baseline levels, can complicate the physician's attempt to use regularly scheduled drug holidays in the management of insomniac patients. Quazepam, a benzodiazepine with a long half-life, has been shown to exhibit carryover effectiveness for the first night or two following withdrawal. This finding suggests a potential utility for an alternate-night drug regimen in which the withdrawal features of the compound serve as a potential benefit. METHOD: A randomized, double-blind, three-compartment, parallel-group design of 5 weeks' duration, comparing quazepam 15 mg, triazolam 0.5 mg, and placebo, was conducted in 65 insomniac subjects. This study was a nonpolysomnographic study utilizing sleep questionnaires. RESULTS: No differences were noted between quazepam and triazolam on treatment nights. Evidence of carryover effectiveness with quazepam and rebound effects with triazolam were noted on off-treatment nights. CONCLUSION: The efficiency of alternate-night therapy with quazepam should be rigorously evaluated using polysomnographic determinations.

Anti-Anxiety Agents↗