Cross-over trial

The cross-over trial was mentioned in the previous section as one example of a within-patient design. In order to discuss some issues associated with these designs we will consider the simplest form of cross-over trial two treatments A and B and two treatment periods I and II. 

It is important therefore to only use these designs when you can be sure that carry-over effects will not be seen. Introducing a washout period between period I and period II can help to eliminate carry-over so that when the subject enters period II their disease condition is similar to what it was at the start of period I. Cross-over designs should not be used where there is the potential to affect the underlying disease state. ICH E9 is very clear on the use of these designs. 

ICH E9 (1998) Note for Guidance on Statistical Principles for Clinical Trials  

The cross-over design is used extensively in phase I trials in healthy volunteers to compare different formulations in terms of their bioequivalence (where there is no underlying disease to affect). They can also be considered in diseases, for 

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Cross-over trials are trials in which patients are allocated to sequences of treatment with the purpose of studying differences between individual treatments. For example, in a study to compare two doses of diclofenac (D1 D2) with placebo (P), patients might be allocated at random and perhaps in equal numbers to sequences as follows  

The patients thus receive each of the three treatments in a different period. In this design each treatment also appears in each period. This property that the treatments are chosen so that treatments appear once in each period and once in each sequence 

Statistical Issues in Drug Development, 2nd Edition. Stephen Senn 2007 John Wiley Sons, Ltd. ISBN 978-0-470-01877-4 

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Because they require fewer subjects and are usually less costly to complete, cross-over trials are commonly used to investigate the effects of phytochemical products. Cross-over designs may be used effectively for studying conditions that are relatively stable so that a similar baseline status can be established at... 

Cross-over trial design Factorial design Hybrid design Large simple clinical trials... 

Jenkins, D.J. A., Kendall, C.W.C., Garsetti, M., et al. (2000). Effects of soy protein food on low density lipoprotein oxidation and ex vivo sex hormone receptor activity -a controlled cross over trial, Metabolism, 49, 537-543. 

Israel E, ChinchUli VM, Ford JG, et al. (2004) Use of regularly scheduled albuterol treatment in asthma genotype-stratified, randomised, placebo-controlled cross-over trial. Lancet. 364, 1505-1512. 

Jones B and Kenward MG. Design and Analysis of Cross-Over Trials London Chapman-Hall, 1989. 

Consider a two-period, two-treatment cross-over trial in asthma comparing an active treatment (A) and a placebo treatment (B) in which the following PEF (1/min) data, in terms of the value at the end of each period, were obtained (Table 4.1). 

Table 4.1 Data from a cross-over trial in asthma (hypothetical)...

In this context, each patient would be receiving each of the multiple treatments. In the cross-over trial with three treatments this would likely be a three-period, three-treatment design and patients would be randomised to one of the six sequences ABC, ACB, BAC, BCA, CAB or CBA. Although there are again ways of asking a simultaneous question relating to the equality of the three treatment means through an analysis of variance approach this is unlikely to be of particular relevance questions of real interest will concern pairwise comparisons. 

Senn S (1997) Statistical Issues in Drug Development Chichester. John WUey Sons, Ltd Senn S (2002) Cross-Over Trials in Clinical Research (2nd edn) Chichester John WUey Sons Senn S (2003) Disappointing dichotomies. Pharmaceutical Statistics, 2, 239-240 Sherman DG, Atkinson RP, Chippendale T et al (2000) Intravenous ancrod for treatment of acute ischemic stroke the STAT study a randomised controUed trial. Journal of the American Medical Association, 283, 2395-2403... 

Messenheimer, J., Ramsay, R.E., Willmore, L.J., Leroy, R.E, Zielinski, J.J., Mattson, R., Pellock, J.M., Valakas, A.M., Womble, G., and Risner, M. (1994) Lamotrigine therapy for partial seizures a multicenter, placebo-controlled, double-blind, cross-over trial. Epilepsia 35 113-21. 

Denicoff KD, Smith-Jackson E, Disney E, et al Comparative prophylactic efficacy of lithium, carbamazepine, and the combination in the treatment of bipolar affective illness. J Chn Psychiatry 58 470-478, 1997 DeNinno MP, Schrenleber R, Mackenzie R, et al A68930 a potent agonist selective for the dopamine Dj receptor. Eur J Pharmacol 199 209-219, 1991 Dennerstein L, Spencer-Gardner C, Gotts G, et al Progesterone and the premenstrual syndrome a double-blind cross-over trial. BMJ 290 1617-1621, 1985... 

Lindholm A, McEwen J, Riis AP. Improved postprandial glycemic control with insulin aspart. A randomized double-blind cross-over trial in type 1 diabetes. Diabetes Care 1999 22(5) 801-5. 

Chevassus H, Mourand I, Molinier N, Lacarelle B, Brun JF, Petit P. Assessment of single-dose benzodiazepines on insulin secretion, insulin sensitivity and glucose effectiveness in healthy volunteers a double-blind, placebo-con-trolled, randomised, cross-over trial. BMC Clin Pharmacol 2004 4(3) 1-10. 

Wettschureck, N, Lee, E, Libutti, SK, Offermanns, S, Robey, PG and Spiegel, AM, 2006, Parathyroid-specific double knockout of Gq- and Gll- alpha subunits leads to a phenotype resembling germline knockout of the extracellular Ca+ +-sensing receptor, Mol Endocrinol Winer, KK, Yanovski, JA, Sarani, B and Cutler, GB, Jr., 1998, A randomized, cross-over trial of once-daily versus twice-daily parathyroid hormone 1—34 in treatment of hypoparathyroidism, J Clin Endocrinol Metab 83 3480-3486... 

Fluoxetine is a selective serotonin-reuptake inhibitor (SSRI) that produces a net increase in (post-synaptic motor neuron) serotonin delivery after 4-6 weeks of use. A double-blind, randomized cross-over trial compared fluoxetine to the tricyclic antidepressant agent protriptyline and placebo in 12 patients with sleep-disordered breathing [52], The group apnea-hypopnea index (AHI) improved with fluoxetine compared to placebo, but there was great variability of response and other measures of disordered sleep did not change. These potentially beneficial results in a small number of patients need to be replicated in well-designed larger studies to support a useful role in clinical practice. 

Mirtazapine is an antidepressant that increases both serotonin and noradrenaline by blockade of central a2 auto- and heteroreceptors mirtazapine also blocks 5-HT2 and 5-HT3 serotonin receptor subtypes, and that former property may induce slow-wave sleep. Systemic administration of mirtazapine has been shown to increase genioglossus muscle activity in anesthetized rats in a dose-dependent manner [55]. In a randomized, double-blind, cross-over trial of ten patients with OSA, mirtazapine at a dose of 15 mg reduced the AHI by 50 %, and the arousal index by some 29 % [56], Side-effects with use of mirtazapine include somnolence and hyperphagia/weight gain. 

In contrast to the parallel group design, in which a given individual receives only one of the two treatments, subjects in a cross-over trial receive both treatments... 

Senn, S., 2002, Cross-over trials in clinical research, 2nd Edition, John Wiley Sons. 

Parmigiani Modeling in Medical Decision Making A Bayesian Approach Senn Cross-over Trials in Clinical Research, Second Edition Senn Statistical Issues in Drug Development... 

Korting, H.C. et al., Influence of repeated washings with soap and synthetic detergents on pH and resident flora of the skin of forehead and forearm. Results of a cross-over trial in health probationers, Acta Derm. Venereol., 67, 41, 1987. 

Many experiments could be carried out either as paired or unpaired studies. For example the rifampicin/theophylline experiment (Table 6.1) was performed on an unpaired basis -15 people received one treatment and a separate group of 15 received the other. This is referred to as a parallel groups trial. We could have used a paired structure, with 15 subjects receiving one treatment on one occasion and the other treatment at some other time (a cross over trial). The paired alternative would almost certainly have been a lot more powerful. However, it does not follow automatically that we should always be looking for a paired experimental design. The following points need to be born in mind ... 

Tugal O, Yazici KM, Yagcioglu AE, Gogus A. 2004. A doubleblind, placebo controlled, cross-over trial of adjunctive donepezil for cognitive impairment in schizophrenia. Int J Neuropsychopharmacol 7 117-123. 

Muller C, Pongratz S, Pidlich J, et al. (1998) Treatment of pruritus in chronic liver disease with the 5-hydroxytryptamine receptor type 3 antagonist ondansetron A randomized, placebo-controlled, double-blind cross-over trial. Eur Gastroenterol Hepatol 10 865-870. 

Di Martino, P. Agniel, R. David, K. Templer, C. Gaillard, J.L. Denys, P. Botto, H. 2006. Reduction of Escherichia coli adherence to uroepithelial bladder cells after consumption of cranberry juice a double-blind randomized placebo-controlled cross-over trial. World J. Urol. 24 21-27. 

Ishikawa et al. (70), in a double-blind, cross-over trial in hypercholesterolemic patients, demonstrated that GLA lowered low-density lipoprotein cholesterol and apolipoprotein B in plasma and increased HDLC levels without affecting the levels of total cholesterol. Jantti et al. (71) observed a decrease in plasma... 

Cantello R, Riccio A, Gilli M, Delsedime M, Scarzella L, Aguggia M, Bergamasco B. Bornaprine vs placebo in Parkinson disease double-blind controlled cross-over trial in 30 patients. Ital J Neurol Sci 1986 7(1) 139 3. 

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