Randomization cross-over trials

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. 

The effects of ketoconazole 200 mg on the pharmacokinetics of nisoldipine 5 mg have been investigated in a randomized, cross-over trial (34). Pretreatment with and concomitant administration of ketoconazole resulted in 24-fold and 11-fold increases in the AUC and C ax of nisoldipine, respectively. The ketoconazole-induced increase in plasma concentrations of the metabolite M9 was of similar magnitude. Thus, ketoconazole and other potent inhibitors of CYP3A should not be used concomitantly with nisoldipine. 

Ashwell SG, Amiel SA, Bilous RW, Dashora U, Heller SR, Hepburn DA, Shutler SD, Stephens JW, Home PD. Improved glycaemic control with insulin glargine plus insulin lispro a multicentre, randomized, cross-over trial in people with Type 1 diabetes. Diabet Med 2006 23(3) 285-292. 

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. 

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. 

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. 

There appears to be a strong link between arterial compliance or stiffness and atherosclerosis and systolic hypertension. In humans, supplementation with soy protein or isoflavones appears to improve com-pliance. In one placebo controlled, randomized, cross-over clinical trial on peri- and postmenopausal women, treatment with 80 mg/day purified soy isoflavones for 5 weeks resulted in improvement of ca. 26% in systemic arterial compliance, even though there was no reduction in blood lipids. Only one study demonstrated a significant decrease in blood pressure, reported in 51 non-hypertensive women after ingestion of 34 mg/day isoflavones,but other studies failed to show a significant effect. ... 

Bruera E, Belzile M, Pituskin E, Fainsinger R, Darke A, Harsanyi Z, Babul N, Ford I. Randomized, double-blind, cross-over trial comparing safety and efficacy of oral controlled-release oxycodone with controlled-release morphine in patients with cancer pain. J Chn Oncol 1998 16(10) 3222-9. 

Brockmoller and colleagues [217] included 13 healthy volunteers in a fourfold cross-over trial. Single doses of 900 mg, 1800 mg and 3600 mg of the methanolic Hypericum extract LI 160 and placebo were administered to the subjects in a randomized sequence. Before and 4 hours after drug intake, when the plasma concentrations of hypericin 1 and... 

Schulz and Jobert [229] investigated the influence of the Hypericum extract LI 160 on the structure of sleep. Twelve elderly female volunteers were included in a double-blind cross-over trial and treated in random sequence with 3 x 300 mg per day of Hypericum extract and placebo. Both treatment periods lasted 4 weeks with a 2-week washout period in between. Eight-hour sleep recording sessions took place during the night before the start and following the last day of each treatment period. 

Schmidt and coworkers [269] tested the pharmacodynamic interaction of Hypericum and alcohol. They included 32 healthy young volunteers of both sexes in a cross-over trial. In a randomized sequence, the subjects received 3 x 300 mg/day of the Hypericum extract LI 160 for 7 days and placebo for another 7 days. On day 7 and day 14 they underwent different tests of reaction time and psychomotor function after oral intake of individually calculated amounts of alcohol resulting in blood concentrations between 45 and 80 ml/1. 

Randomization is a word which is used to describe the allocation at random (using aleatory devices, such as, for example, dice, cards, lots or random number tables or generators) of treatments to the units in an experiment. In a clinical trial these units are most typically the patients, although occasionally a centre might be treated as a unit, and in cross-over trials, in which patients may receive two or more treatments, a treatment episode is the basic experimental unit. 

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 ... 

Palmer DJ, Gold MS, Makrides M (2005). Effect of cooked and raw egg consumption on ovalbumin content of human milk a randomized, double-blind, cross-over trial. Clin. Exp. Allergy, 35 173-178. 

Kendall, C.W.C., Jenkins, D.J.A., Marchie, A., Parker, T., and Connelly, P., Dose response of almonds on coronary heart disease risk factors-blood lipids, oxidized LDL, Lp(a), homocysteine and pulmonary nitric oxide A randomized controlled cross-over trial. Circulation, 106, 1327-1332, 2002. 

Thomas HD, Porter DJ, Bartelink I, Nobbs JR, Cole M, Elliott S, Newell DR, Calvert AH, Highley M, Boddy AV, Randomized cross-over clinical trial to study potential pharmacokinetics interactions between cisplatin or carboplatin and etoposide. BrJ Clin Pharmacol (2002) 53, 83-91. 

Pomier Layrargues G, Giguere JF, Lavoie J, Perney P, Gagnon S, D Amour M, Wells J, Butterworth RF. Clinical efficacy of benzodiazepine antagonist RO 15—1788 (flumazenil) in cirrhotic patients with hepatic coma Results of a randomized dot >le-blind placebo-conttoUed cross-over trial. Hepatology, 19, 32-37, 1994... 

Van den Bogaard V, Draijer R, Westerhof BE, Van den Meiracker AH, Van Montfrans GA, Van den Born B-JH. Effects on peripheral and central blood pressure of cocoa with natural or high dose theobromine. A randomized, double-blind cross-over trial. Hypertension 2010 56 839-46. 

In 81-year-old subjects, high plasma TNF-a was associated with atherosclerosis but not with TC, LDL, and BMI, and was weakly correlated with TG, leukocytes, CRP, and low HDL/TC ratio (154). The presence of antinuclear antibodies is substantially more prevalent among subjects with severe coronary atherosclerosis than those with normal coronary arteries (7 55 j. On the other hand, in a double-blind randomized placebo controlled cross over trial of healthy men, acute systemic inflammation augmented local forearm tPA release suggesting it can invoke a protective response (156). 

Harbo T, Andersen H, Hess A, Hansen K, Sindrup SH, Jakobsen J. Subcutaneous versus intravenous immunoglobulin in multifocal motor neuropathy a randomized, single-blinded cross-over trial. Eur J Neurol 2009 16(5) 631-8. 

Halpem, G.M., Prindiville, T., Blankenburg, M., Hsia, T., and Gershwin, M.E. 1996. Treatment of irritable bowel syndrome with Lacteol Eort A randomized, double-hlind, cross-over trial. Am J GastroerAetoX 9I(Z), 1579-1585. 

Mizukami K, Murakami K, Yamauchi M, Matsunari O, Ogawa R, Nakagawa Y, et al. Evaluation of selective cyclooxygenase-2 inhibitor-induced smaU bowel injury randomized cross-over study compared with loxoprofen in healthy subjects. Dig Endosc May 2013 25(3) 288-94. Maehata Y, Esaki M, Morishita T, Kochi S, Endo S, Shikata K, et al. SmaU bowel injury induced by selective cyclooxygenase-2 inhibitors a prospective, double-bUnd, randomized clinical trial comparing celecoxib and meloxicam. J Gastroenterol April 2012 47(4) 387-93. 

Johnston C, Saradno M, Kuntz S, Magaret A, Selke S, Huang ML, et al. Standard-dose and high-dose antiviral therapy for short episodes of genital HSV-2 reactivation three randomized, open-label, cross-over trials. Lancet 2012 379(9816) 641-7. 

Cross-over design trials represent an adaptation of randomized control trials in which each participant acts as his/her own control. In the simplest scenario, each participant will receive either a placebo or the test drug for the first half of the trial and will receive the alternative treatment for the second half. The order of placebo versus test drug for any individual is randomized. Hence, at any time point, approximately half the test participants will be receiving the placebo and the other half the test substance. 

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