Two-treatment Crossover Trial Research Articles

Stress in client-owned dogs related to clinical exam location: a randomised crossover trial.

To quantify the effects of wellness examinations conducted in the common treatment area on fear, anxiety and stress indicators in client-owned dogs. The study was a prospective, non-blinded, randomised, two-period two-treatment crossover trial. Client-owned healthy adult dogs presenting for wellness or dental evaluations at a single veterinary teaching hospital received three consecutive rapid assessment exams; a baseline exam (owner present), followed by two identical physical exams differing in location and presented in random order (isolated exam room with owner present versus common treatment area, owner absent). Primary endpoints were a cumulative fear, anxiety and stress score for five standardised behaviours and heart rate (bpm) measured for each exam. Forty-four dogs were enrolled. Modal fear, anxiety and stress score at baseline was 1 of 5, indicating none to mild stress. Both fear, anxiety and stress and heart rates measured in the common treatment area were clinically elevated relative to assessments conducted in the exam room. Relative to baseline, animals examined in the common treatment area showed increased fear, anxiety and stress (+2.6 units, se 0.5; P<0.0001) and heart rate (20 bpm, 95% confidence interval 13, 28; P<0.0001. Twenty-eight dogs (64%) exhibited fear, anxiety and stress scores ≥3 of 5 (moderate to severe stress) in the common treatment area, compared to 19 (43%) during exam room assessments. Stress assessments in this study may have been biased by inability to blind assessors to location. However, stress metrics showed clinically significant, consistent and directionally symmetrical increases when dogs were examined in the common treatment area. When physical exam locations are highly stimulating, dogs may experience increased stress and anxiety, with detrimental effects on clinical assessments and behavioural welfare. Whenever possible, physical exams and procedures should take place in low-stress environments with the owner present.

Evaluation of clinical examination location on stress in cats: a randomized crossover trial.

The objective of this study was to quantify the effects of owner separation and physical examination location on fear, anxiety and stress (FAS) behavioral indicators in cats. The study was a prospective, non-blinded, randomized, two-period, two-treatment crossover trial. Healthy adult cats presenting for wellness or dental evaluations at a single veterinary teaching hospital received three physical examinations: a baseline assessment (owner present) followed by physical examinations in both a treatment area (owner absent [TAOA]) and an examination room (owner present [EROP]). The physical examination sequence order was randomized. Low-stress handling techniques were used for all examinations. The primary endpoints were heart rate (HR; beats per min [bpm]) and total FAS scores. HR was measured by auscultation, and FAS by five specific behaviors scored as 0/1 and summed for each assessment period. Twenty-one healthy cats were enrolled. HR measured at entry (baseline) was a significant determinant of subsequent HR readings. HR measured during examinations conducted in both EROP and TAOA were elevated to levels indicative of stress (>180 bpm). HR was significantly higher for TAOA relative to EROP (30 bpm, 95% confidence interval 18-43; P <0.001). Behavioral FAS scores showed no statistically significant effects of sequence or room. FAS scores for TAOA assessments were clinically elevated relative to baseline (1.5 FAS, SE 0.7; P = 0.05); EROP FAS scores relative to baseline did not differ statistically (0.5 units, SE = 0.5; P = 0.43). Owner separation coupled with physical examination location can result in clinically significant increases in perceived stress in cats, and compromise vital sign assessments. Whenever possible, physical examinations and procedures should take place with the owner present with separation from unfamiliar dogs and cats.

Pharmacokinetics of prednisolone in children: an open-label, randomised, two-treatment cross-over trial investigating the bioequivalence of different prednisolone formulations in children with airway disease

IntroductionOne in three Danish children under 3 years of age experience asthma-like symptoms, and one-third will later be diagnosed with asthma. Oral prednisolone is used in various formulations to treat...

Odds ratio based two-stage group sequential analysis for two-treatment two-period crossover trials

We consider a two-treatment and two-period crossover design where the treatment responses are binary. The outcome from each patient under such trial can be represented by a two-component vector which follows a bivariate binomial distribution. We develop a two-stage group sequential test procedure for equivalence based on the estimates of odds ratio. Various error spending functions are studied in this context. Simulation studies are carried out. An illustration with some real data example is also given.

Does Site Matter? Comparing Accuracy and Patient Comfort of Blood Glucose Samples Taken From the Finger and Palm of the Perioperative Patient

This study compared two blood glucose (BG) point of caresampling methods to determine which is least painful yet accurate. The two-period, two-treatment crossover trial compared the traditional fingertip sampling method to a form of alternative site testing (AST), palm of the hand. Subjects received both methods of BG sampling to compare comfort and accuracy. They were randomly assigned to determine which method was used first. Pain rating (0 to 10) and glucose results for both methods were documented. Results indicated that pain rating was significantly lower with AST (1.65) than with the standard site (2.83) (P<.001). There was no significant difference in mean glucose measurements between standard care (150mg/dL) and AST (149mg/dL). The numbers were closely correlated (r=0.9815). Findings support AST via the palm of the hand as an accurate and less painful method of obtaining BG results on diabetic patients.

Pediatric Tape: Accuracy and Medication Delivery in the National Park Service.

IntroductionThe objective is to evaluate the accuracy of medication dosing and the time to medication administration in the prehospital setting using a novel length-based pediatric emergency resuscitation tape.MethodsThis study was a two-period, two-treatment crossover trial using simulated pediatric patients in the prehospital setting. Each participant was presented with two emergent scenarios; participants were randomized to which case they encountered first, and to which case used the National Park Service (NPS) emergency medical services (EMS) length-based pediatric emergency resuscitation tape. In the control (without tape) case, providers used standard methods to determine medication dosing (e.g. asking parents to estimate the patient’s weight); in the intervention (with tape) case, they used the NPS EMS length-based pediatric emergency resuscitation tape. Each scenario required dosing two medications (Case 1 [febrile seizure] required midazolam and acetaminophen; Case 2 [anaphylactic reaction] required epinephrine and diphenhydramine). Twenty NPS EMS providers, trained at the Parkmedic/Advanced Emergency Medical Technician level, served as study participants.ResultsThe only medication errors that occurred were in the control (no tape) group (without tape: 5 vs. with tape: 0, p=0.024). Time to determination of medication dose was significantly shorter in the intervention (with tape) group than the control (without tape) group, for three of the four medications used. In case 1, time to both midazolam and acetaminophen was significantly faster in the intervention (with tape) group (midazolam: 8.3 vs. 28.9 seconds, p=0.005; acetaminophen: 28.6 seconds vs. 50.6 seconds, p=0.036). In case 2, time to epinephrine did not differ (23.3 seconds vs. 22.9 seconds, p=0.96), while time to diphenhydramine was significantly shorter in the intervention (with tape) group (13 seconds vs. 37.5 seconds, p<0.05).ConclusionUse of a length-based pediatric emergency resuscitation tape in the prehospital setting was associated with significantly fewer dosing errors and faster time-to-medication administration in simulated pediatric emergencies. Further research in a clinical field setting to prospectively confirm these findings is needed.

A double-blind, randomized, placebo-controlled trial studying the effects of Saccharomyces boulardii on the gastrointestinal tolerability, safety, and pharmacokinetics of miglustat

BackgroundGastrointestinal (GI) disturbances such as diarrhea and flatulence are the most frequent adverse effects associated with miglustat therapy in type 1 Gaucher disease (GD1) and Niemann-Pick disease type C (NP-C), and the most common recorded reason for stopping treatment during clinical trials and in clinical practice settings. Miglustat-related GI disturbances are thought to arise from the inhibition of intestinal disaccharidases, mainly sucrase isomaltase. We report the effects of a co-administered dietary probiotic, S. boulardii, on the GI tolerability of miglustat in healthy adult subjects.MethodsIn a double-blind, placebo-controlled, two-period, two-treatment cross-over trial, healthy adult male and female subjects were randomly allocated to treatment sequences, A–B and B–A (treatment A - miglustat 100 mg t.i.d. + placebo; treatment B - miglustat 100 mg t.i.d. + S. boulardii [500 mg, b.i.d.]). GI tolerability data were collected in patient diaries. The primary endpoint was the total number of ‘diarrhea days’ (≥3 loose stools within a 24-h period meeting Bristol Stool Scores [BSS] 6–7) based on WHO criteria. Secondary endpoints comprised numerous other diarrhea and GI tolerability indices.ResultsTwenty-one subjects received randomized therapy in each treatment sequence (total N = 42), and overall, 37 (88 %) subjects completed the study. The total number of diarrhea days was <1.5 for both treatment sequences, and approximately 60 % of subjects did not experience diarrhea during either treatment period. The mean (SD) number of diarrhea days was lower with miglustat + S. boulardii (0.8 [2.4] days) than with miglustat + placebo (1.3 [2.4] days), but the paired treatment difference was not statistically significant (−0.5 [2.4] days; p = 0.159). However, a significant treatment difference (−0.7 [1.9]; p < 0.05) was identified after post hoc exclusion of a clear outlier who had a very high number of diarrhea days (n = 13) and inconsistent GI tolerability reporting. The incidence of the GI AEs was higher with miglustat + placebo (82 %) than with miglustat + S. boulardii (73 %). There were no between-treatment differences in miglustat pharmacokinetics.ConclusionsAlthough the primary endpoint was not met, the results of the post-hoc analysis suggest that co-administration of miglustat with S. boulardii might improve GI tolerability.

A recommended analysis for 2 × 2 crossover trials with baseline measurements.

In many two-period, two-treatment (2 × 2) crossover trials, for each subject, a continuous response of interest is measured before and after administration of the assigned treatment within each period. The resulting data are typically used to test a null hypothesis involving the true difference in treatment response means. We show that the power achieved by different statistical approaches is greatly influenced by (i) the 'structure' of the variance-covariance matrix of the vector of within-subject responses and (ii) how the baseline (i.e., pre-treatment) responses are accounted for in the analysis. For (ii), we compare different approaches including ignoring one or both period baselines, using a common change from baseline analysis (which we advise against), using functions of one or both baselines as period-specific or period-invariant covariates, and doing joint modeling of the post-baseline and baseline responses with corresponding mean constraints for the latter. Based on theoretical arguments and simulation-based type I error rate and power properties, we recommend an analysis of covariance approach that uses the within-subject difference in treatment responses as the dependent variable and the corresponding difference in baseline responses as a covariate. Data from three clinical trials are used to illustrate the main points.

Effect of Caffeinated Soft Drinks on Salivary Flow.

Soft drinks containing caffeine have been associated with more aggressive forms of dental decay. Cariogenicity of caffeinated soft drinks may be attributed to the effect of caffeine on salivary flow. This study assessed whether caffeinated soft drinks produced short-term oral dryness in healthy adults. The authors collected saliva on two separate days from 35 participants before and one hour after drinking a soft drink. On one of the days the soft drink was caffeinated and on the other day it was not. Saliva collection involved 15 minutes unstimulated whole saliva, 5 minutes paraffin-stimulated whole saliva, and 10 seconds labial minor salivary gland output. Unstimulated and stimulated flow rates slightly increased and minor gland output slightly decreased one hour after the soft drink consumption regardless of caffeine content. These changes were not statistically significant (two-period two-treatment crossover trial using two-stage Grizzle model, p>0.05). A linear mixed model statistic did not show the caffeine effect on salivary flow rate. Caffeinated soft drink consumption had no significant effect on salivary flow rate after one hour by any of the three measures employed in this study. Caffeine's contribution to the cariogenicity of soft drinks is likely by centrally-mediated effects on consumption patterns.

Adaptive Crossover Design for Normal Responses

In a response-adaptive design, we review and update the trial on the basis of outcomes in order to achive a specific goal. In clinical trials our goal is to allocate a larger number of patients to the better treatment. In the present paper, we use a response adaptive design in a two-treatment two-period crossover trial where the treatment responses are continuous. We provide probability measures to choose between the possible treatment combinations AA, AB, BA, or BB. The goal is to use the better treatment combination a larger number of times. We calculate the allocation proportions to the possible treatment combinations and their standard errors. We also derive some asymptotic results and provide solutions on related inferential problems. The proposed procedure is compared with a possible competitor. Finally, we use a data set to illustrate the applicability of our proposed design.

Effect of Phenylephrine and Ephedrine Bolus Treatment on Cerebral Oxygenation in Anaesthetized Patients

Meng, L.*; Cannesson, M.*; Alexander, B.S.*; Yu, Z.†; Kain, Z.N.*; Cerussi, A.E.‡; Tromberg, B.J.‡; Mantulin, W.W.‡ Author Information

Effect of phenylephrine and ephedrine bolus treatment on cerebral oxygenation in anaesthetized patients

How phenylephrine and ephedrine treatments affect global and regional haemodynamics is of major clinical relevance. Cerebral tissue oxygen saturation (Sct(O2) )-guided management may improve postoperative outcome. The physiological variables responsible for Sct(O2) changes induced by phenylephrine and ephedrine bolus treatment in anaesthetized patients need to be defined. A randomized two-treatment cross-over trial was conducted: one bolus dose of phenylephrine (100-200 µg) and one bolus dose of ephedrine (5-20 mg) were given to 29 ASA I-III patients anaesthetized with propofol and remifentanil. , mean arterial pressure (MAP), cardiac output (CO), and other physiological variables were recorded before and after treatments. The associations of changes were analysed using linear-mixed models. The CO decreased significantly after phenylephrine treatment [▵CO = -2.1 (1.4) litre min(-1), P<0.001], but was preserved after ephedrine treatment [▵CO = 0.5 (1.4) litre min(-1), P>0.05]. The was significantly decreased after phenylephrine treatment [▵ = -3.2 (3.0)%, P<0.01] but preserved after ephedrine treatment [▵ = 0.04 (1.9)%, P>0.05]. CO was identified to have the most significant association with (P<0.001). After taking CO into consideration, the other physiological variables, including MAP, were not significantly associated with (P>0.05). Associated with changes in CO, decreased after phenylephrine treatment, but remained unchanged after ephedrine treatment. The significant correlation between CO and implies a cause-effect relationship between global and regional haemodynamics.

Renal Insufficiency Has No Effect on the Pharmacokinetics of Vicriviroc in a Ritonavir-Containing Regimen

Vicriviroc is a small-molecule CCR5 antagonist currently in development for the treatment of HIV in patients on a regimen containing a ritonavir-boosted protease inhibitor. As renal disease and renal dysfunction are prevalent in the HIV-infected population, patients with varying degrees of renal insufficiency may receive vicriviroc, which is metabolized by cytochrome P450 (CYP) 3A4. The present study therefore examined the impact of renal insufficiency on the pharmacokinetics and safety of vicriviroc alone and in the presence of ritonavir, a strong CYP3A4 inhibitor. This study was an open-label, randomized, two-treatment crossover trial conducted in HIV-negative subjects with haemodialysis-dependent end-stage renal disease (ESRD) and healthy subjects with normal renal function matched by age, height, bodyweight and sex. Subjects received a single dose of vicriviroc 75 mg alone in one period, and in another period they received a single dose of vicriviroc 15 mg after 4 days of ritonavir 100 mg once daily. Ritonavir treatment was then continued for an additional 13 days. The two trial periods were separated by an interval of at least 3 weeks. The primary endpoints were the log-transformed area under the plasma concentration-time curve (AUC) and the maximum plasma concentration (C(max)), and the 90% confidence intervals (CIs) of the mean differences between subjects with ESRD and matched healthy subjects. The protocol provided the option of dose modification and further study if the vicriviroc C(max) and AUC values were at least twice as high in subjects with ESRD compared with healthy subjects, or if warranted by other safety and tolerability observations. Twelve subjects (six with ESRD, six healthy) completed the study. When vicriviroc was administered alone, the mean vicriviroc C(max) and AUC ratio estimates (90% CI) for subjects with ESRD versus healthy subjects were 74% (53, 103) and 84% (49, 145), respectively. When ritonavir was added to the regimen, the ratio estimates (90% CI) were 81% (59, 111) and 134% (105, 171), respectively. Ritonavir plasma concentrations were substantially higher in subjects with ESRD than in healthy subjects. Treatment-emergent adverse events considered possibly or probably related to treatment occurred only during the ritonavir period of the study and in one healthy subject and two subjects with ESRD; all were of mild or moderate severity. ESRD had no clinically relevant impact on exposure of vicriviroc when vicriviroc was administered alone or in the presence of ritonavir. In this single-dose study, vicriviroc was well tolerated both by healthy subjects and by those with ESRD. Dose adjustment of vicriviroc is therefore not necessary in renally impaired populations.

Meta-analyses involving cross-over trials: methodological issues

Background Meta-analysis of randomized controlled trials (RCTs) is usually based on trials where patients are randomized individually into two different, parallel, treatment groups. This paper concentrates on RCTs of a different design—two-period, twotreatment cross-over trials. Methods The characteristics of these trials are outlined, with detailed examples of methods for analysis for both continuous and binary data. These case studies are then extended into the context of a meta-analysis. The Cochrane Library was surveyed to assess current practice for synthesis. Results Methods are described for continuous and binary data for use both when the necessary paired data are given and also when they need to be calculated or imputed, and some suggestions are provided to help people wishing to synthesize data from cross-over trials into meta-analyses. The survey suggested that about 8% of the trials in the Cochrane library were cross-over trials and 18% of the reviews referred to such trials, although there was no consistent approach to their inclusion into the reviews. Conclusions Methods do exist for including valuable information from two-period, twotreatment cross-over trials into quantitative reviews. However, poor reporting of cross-over trials will often impede attempts to perform a meta-analysis using the available methods.

Analysis of a three-period two-treatment pharmacokinetic study to assess scaled average bioequivalence

Abstract In the past years, various approaches for assessing bioequivalence of so-called 'highly variable drugs' have been debated. These are drugs whose pharmacokinetic profiles vary considerably when given to the same subject. As a consequence of the high variability, average bioequivalence between two such drugs can only be shown with an unfeasibly high number of subjects. Therefore, regulatory agencies generally agree that the criterion of average bioequivalence warrants adjustment for highly variable drugs. The mainstream of the most recent discussion favours an approach that is called scaled average bioequivalence. With this approach, the usual criterion of average bioequivalence is scaled by the within-subject standard deviation of the pharmacokinetic parameter in question. A parsimonious design for evaluating scaled average bioequivalence is a three-period two-treatment crossover trial where the reference drug is given twice and the investigational drug is given once to each subject. In this paper...

A randomised crossover trial of patient controlled intranasal fentanyl and oral morphine for procedural wound care in adult patients with burns

This study sought to compare the analgesic efficacy and safety of patient controlled intra-nasal (PCIN) fentanyl with oral morphine for procedural wound care in burns patients. A randomised double-blind placebo controlled, two period, two-treatment crossover trial was conducted within the Burns Unit of a major teaching hospital in Perth, Western Australia. Patients requiring identical wound care procedures on two consecutive mornings (and not prescribed intravenous analgesia) were randomised to receive either PCIN fentanyl with oral placebo or oral morphine with intranasal placebo on 1 day, followed by the alternate active drug on the following day. Twenty-six patients (22 males), aged between 18 and 69 years (35.5±12.4 years), with total body surface burns (TBSA) range 1–25% (6.9±4.5%), indicated their level of pain on a 10 point (0–10) numeric scale at various time periods before, during and after the procedure. A mean total dose of 1.48±0.57 μg/kg of PCIN fentanyl and 0.35±0.12 mg/kg of oral morphine was administered. No statistically significant difference was found between the pain scores recorded for patients during the procedure with PCIN fentanyl compared to that with oral morphine ( mean difference =−0.75 , 95% CI=−1.97 to 0.47, P=0.22). Two patients experienced hypotension during the procedure—both had received active oral morphine. No patients experienced respiratory depression or a significant drop in oxygen saturation. There were four episodes (in three patients) where ‘rescue analgesia’ for severe pain was required – two episodes involving oral morphine and two involving PCIN fentanyl. It was concluded that PCIN fentanyl is similar in efficacy and safety to oral morphine for relief of procedural wound care pain in burns patients.

Meta-analysis combining parallel and cross-over clinical trials. III: The issue of carry-over.

In meta-analysis combining results from parallel and cross-over trials, there is a risk of bias originating from the carry-over effect in cross-over trials. When pooling treatment effects estimated from parallel trials and two-period two-treatment cross-over trials, meta-analytic estimators of treatment effect can be obtained from the combination of parallel trial results either with cross-over trial results based on data of the first period only or with cross-over trial results analysed with data from both periods. Taking data from the first cross-over period protects against carry-over but gives less efficient treatment estimators and may lead to selection bias. This study evaluates in terms of variance reduction and mean square error the cost of calculating meta-analysis estimates with data from the first period instead of data from the two cross-over periods. If the information on cross-over sequence is available, we recommend performing two combined design meta-analyses, one using the first cross-over period data and one based on data from both cross-over periods. To investigate simultaneously the statistical significance of these two estimators as well as the carry-over at meta-analysis level, a method based on a multivariate analysis of the meta-analytic treatment effect and carry-over estimates is proposed.

Meta-analyses involving cross-over trials: methodological issues.

Meta-analysis of randomized controlled trials (RCTs) is usually based on trials where patients are randomized individually into two different, parallel, treatment groups. This paper concentrates on RCTs of a different design-two-period, two-treatment cross-over trials. The characteristics of these trials are outlined, with detailed examples of methods for analysis for both continuous and binary data. These case studies are then extended into the context of a meta-analysis. The Cochrane Library was surveyed to assess current practice for synthesis. Methods are described for continuous and binary data for use both when the necessary paired data are given and also when they need to be calculated or imputed, and some suggestions are provided to help people wishing to synthesize data from cross-over trials into meta-analyses. The survey suggested that about 8% of the trials in the Cochrane library were cross-over trials and 18% of the reviews referred to such trials, although there was no consistent approach to their inclusion into the reviews. Methods do exist for including valuable information from two-period, two-treatment cross-over trials into quantitative reviews. However, poor reporting of cross-over trials will often impede attempts to perform a meta-analysis using the available methods.

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 satidfied.