Cross-over studies

The carryover effect is only one type of issue that may complicate the interpretation of results from a cross-over study. A more complete description of the potential pitfalls in the analysis of cross-over studies is beyond the scope of this chapter. The reader should simply be aware that, although cross-over studies may be less expensive to conduct than parallel trials initially, they also carry a higher risk of producing results that are fficult or impossible to interpret, thus requiring that the study be repeated to obtain clear results. 

In a traditional, two-way cross-over study, blood samples are taken at predetermined times (e.g., 0.5, 1, 1.5, 3, 6, 9, 12, 24, and 36 hours after dosing). The samples are assayed for drug (and if necessary metabolites). Fortunately, analytical methods, especially HPLC, are now available that make the quantification of many drugs in blood or serum convenient, rapid, and relatively inexpensive. The method selected should normally have an acceptance precision so that concentrations of drug of one tenth Cmax can be reliably quantified. 

Nagtegaal, J. E., Kerkhof, G. A, Smits, M. G., Swart, A. C. van der Meer, Y. G. (1998). Delayed sleep phase syndrome A placebo-controlled cross-over study on the effects of melatonin administered five hours before the individual dim light melatonin onset. J. Sleep Res. 7, 135-43. 

Crossover designs are susceptible to carry-over effects, that is, the treatment effect from the first period has not worn off at the time of conducting the second period. Tests of analysis can detect carry-over effects, but it is too late then to modify the design. Similarly, period effects may confound the interpretation of cross-over studies, that is, the order in which one treatment occurs in a sequence compared with another influences the response to early treatment. Randomisation usually, but not always, precludes the effect. 

Cross-over studies in which one or more panels of 4-6 volunteers receive several doses of active compound, with double blind placebo randomly interposed. The advantage of this design is that before giving a higher dose, the reaction... 

Onofrj, M., Paci, C., D Andreamatteo, G., and Toma, L., (2000) Olanzapine in severe Gilles de la Tourette syndrome a 52-week double-blind cross-over study vs. low-dose pimozide. J Neurol. 247 443 46. 

Ten human subjects received coumarin orally (1 g and 2 g) and intravenously (250 mg) in a randomized cross-over study and their 0-48 h urines were assayed for ortho-hydroxyphenylacetic acid. After intravenous administration, 1.5% (range, 0.3-3.6%)... 

Mitchell JE, Christenson G, Jennings J, et al. A placebo-controlled, double-blind cross-over study of naltrexone hydrochloride in outpatients with normal weight bulimia. J Clin Psychopharmacoi 1989 9 94-97. 

The cross-over study was carried out in two parts. In the first part the subjects were fasted overnight and at 8 a.m. took one capsule with 100 ml of tap water, Food was subsequently withheld for 3 h, after which a standard lunch was served. Blood was sampled (10 ml) just before and 2, 4, 8, 12, 24 and 32 h after dosage. Immediately following each blood sample (except at 0 and 32 h) an X-ray photograph was taken to determine the position of the pellets in the gastrointestinal tract. The X-ray photographs were taken in the supine position and the sites of the alimentary canal numbered as in Table 1. 

Sindrup, S.H., Gram, L.F., Skjold, T., Grodum, E., Brosen, K. Clomipramine vs desipramine vs placebo in the treatment of diabetic neuropathy symptoms. A double-blind cross-over study, Br. J. 

Rompel, H., Bauermeister, P. W. Aetiology of migraine and prevention with carbamazepine (tegretol) results of a double-blind, cross-over study, S. Afr. Med. 1970, 44, 75-78. 

Nikolajsen, L., Gottrup, H., Kristensen, A. G. D., Jensen, T. S. Memantine (a N-methyl-D-aspartate receptor antagonist) in the treatment of neuropathic pain after amputation or surgery a randomized, double-blinded, cross-over study, Anesth. Analg. 2000, 97, 960-966. 

Rosing J, Middeldorp S, Curvers J, Christella M, Thomassen LG, Nicolaes GA, Meijers JC, Bouma BN, Buller HR, Prins MH, Tans G. Low-dose oral contraceptives and acquired resistance to activated protein C a randomised cross-over study. Lancet... 

Meijers JC, Middeldorp S, Tekelenburg W, van den Ende AE, Tans G, Prins MH, Rosing J, Buller HR, Bouma BN. Increased fibrinolytic activity during use of oral contraceptives is counteracted by an enhanced factor Xl-independent down regulation of fibrinolysis a randomized cross-over study of two low-dose oral contraceptives. Thromb Haemost 2000 84(1) 9-14. 

Lalej-Bennis D, Boillot J, Bardin C, Zirinis P, Coste A, Escudier E, Chast F, Peynegre R, Selam JL, Slama G. Efficacy and tolerance of intranasal insulin administered during 4 months in severely hyperglycaemic Type 2 diabetic patients with oral drug failure a cross-over study. Diabet Med 2001 18(8) 614-8. 

We recently investigated whether the administration of a selective serotonin reuptake inhibitor, fluvoxamine, could interfere with the sleep patterns induced after TED. In this double-blind placebo-controlled cross-over study, 12 healthy male volunteers aged 18-40 years were assigned to two treatment conditions tryptophan or sham depletion and fluvoxamine or placebo. During each session, separated by a 2-day wash-out period, subjects took either fluvoxamine or placebo and either tryptophan... 

Fig. 2. Effects of a tryptophan versus a sham depletion on the REM sleep alterations induced by 150 mg fluvoxamine in 12 healthy subjects a double blind placebo-controlled 4-way cross over study...

Cross-over study designs are typically employed in bioequivalence trials. Imagine that the new formulation is called N and the existing formulation is called R (the reference formulation). The two order possibilities for receiving the two drug treatments are NR and RN. Typically, healthy male and female adults participate in these studies, and the treatment orders are appropriately controlled and balanced. Pharmacokinetic parameters are used to represent both safety and efficacy. 

The interoccasion variability (IOV) or intraindividual variability [11] arises when a parameter of the model, e.g. CL, varies within a subject between study occasions. The term occasion can be defined arbitrarily, usually logical intervals for an occasion are chosen, e.g. each dosing interval in multiple dose studies or each treatment period of a cross-over study can be defined as an occasion. To assess the IOV of a specific parameter more than one measurement per individual has to be available per occasion. The IOV can be implemented in the random effect model as described in the following ... 

Gardner and Cowdry (1985) found an increase in dyscontrol in borderline patients taking alprazolam in a double-blind, placebo-controlled cross-over study. The dyscontrol included the following Overdose, severe Overdose, moderate Deep neck cuts Transverse wrist cuts Tried to break own arm Threw chair at child and Arm and head banging jumped in front of car. ... 

A phase I, open-label, randomized, cross-over study to investigate the bioavailability, safety, tolerability and pharmacodynamics following single oral administration of XYZ1234 as capsule and single intravenous administration of XYZ1234 in healthy men. 

This was an open-label, single-dose, randomized, 2-period cross-over study with a minimum washout period of 7 days. Each treatment group received treatment A (10 mg XYZ1234, intravenously administered) and treatment B (25 mg XYZ1234 as capsule, orally administered), once each under fasting conditions. 

In case of two study medications, a sound alternative to a parallel design would be the (complete) cross-over study design. 

Comparison of pharmacokinetics and safety of extended release formulations of 600 mg XYZ1234 with that of an immediate release formulation -a single-center, open-label, cross-over study in healthy men. 

The study was carried out in a single center, open-label, singledose, four period cross-over study design with two independent treatment groups. 

Depatie L, O Driscoll G, Holahan AL, Atkinson V, Thavundayuil J, et al. 2002. Nicotine and behavioral markers of risk for schizophrenia A double-blind, placebo-controlled, cross-over study. Neuropsychopharma-cology27 1056-1070. 

Stryjer R, Strous R, Bar F, Shaked G, Shiloh R, et al. 2004. Donepezil augmentation of clozapine monotherapy in schizophrenia patients a double blind cross-over study. Hum Psychopharmacol 19 343-346. 

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