Randomisation failure

We have just found that, for large molecules, the predicted behaviour is the same whether we use the separable or the non-separable model. Clearly, then, many situations where randomisation failure is thought to be a factor can be examined quite adequately by using the separable approach. One can envisage three such possible situations. Of obvious contemporary interest is the problem of multiphoton dissociation of large... 

Also, as is becoming increasingly recognised [80.J2], multichannel thermal reactions possess considerable potential for showing up departure from strong collision behaviour if such departures from strong collision behaviour arise as the result of a randomisation failure, this model quickly yields the relative fall-off behaviour for the various reaction channels, as an extension of equation (7.7). If there are only two interfering channels, m = 1, 2, the result is [81.P2]... 

Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure myocardial infarction... 

In all of the following the order in the run in which the various materials are analysed should be randomised if possible. A failure to randomise may result in an underestimation of various components of error. 

Cunningham, D. et al.. Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. The Lancet, 352, 1413-1418, 1998. 

Bartlett RH, Roloff DW, Cornell RG, et al. Extracorporeal circulation in neonatal respiratory failure a prospective randomised trial. Paediatrics 1985 76 479-87. 

MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure Metoprolol CR/XL randomised intervention trial in congestive heart failure (MERIT-HF). Lancet. Jun 12 1999 353(9169) 2001-2007. 

Pitt B, Segal R, Martinez FA, Meurers G, Cowley AJ, Thomas I et al. Randomised trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly Study, ELITE). Lancet 1997 349(9054) 747-52. 

Lago RM, Singh PP, Nesto RW. Congestive heart failure and cardiovascular death in patients with prediabetes and type 2 diabetes given thiazolidinediones a meta-analysis of randomised clinical trials. Lancet 2007 370 1129-36. 

Piepoli M, Villani GQ, Ponikowski P, Wright A, Flather MD, Coats AJ. Overview and meta-analysis of randomised trials of amiodarone in chronic heart failure. IntJCard 1998 66(1) 1-10. 

As many of us who are involved in clinical trials will know, the randomised, controlled trial is a relatively new invention. As pointed out by Pocock (1983) and others, very few clinical trials of the kind we now regularly see were conducted prior to 1950. It took a number of high profile successes plus the failure of alternative methodologies to convince researchers of their value. 

A placebo-controlled randomised trial reported by Packer et al. (2001) investigated the effect of carvedilol on survival time in severe heart failure. Figure 13.1 shows the survival curve for each of the two treatment groups following the early termination of the trial at a planned interim analysis. 

Figure 13.1 Kaplan-Meier survival curves in placebo and carvedilol groups (Packer M, Coats AJS, Fowler MB, et al. for the Carvedilol Prospective Randomised Cumulative Survival Study Group, Effect of carvedilol on survival in severe chronic heart failure. New England Journal of Medicine, 344, 1651-1658. (2001) Massachusetts Medical Society.)...

This was an open-label, parallel group, randomised trial in patients with chronic HIV-1 infection reported by van Leth et al. (2004). The primary endpoint was treatment failure, a composite endpoint based on virology, disease progression or therapy change. Initially patients were randomised equally to one of the following three groups ... 

J3. Johnson, C. D., Kingsnorth, A. N., Imrie, C. W., McMahon, M. J., Neoptolemos, J. P., McKay, C., Toh, S. K., Skaife, P., Leeder, P. C., Wilson, P., Larvin, M., and Curtis, L. D., Double blind, randomised, placebo controlled study of a platelet activating factor antagonist, Lexipafant, in the treatment and prevention of organ failure in predicted severe acute pancreatitis. Gut 48, 62-69... 

Poole-Wilson PA, Swedberg K, Cleland JG, et al, Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET) randomised controlled trial, Lancet 2003 362 7-13. 

Pitt B, Poole-Wilson PA, Segal R, et al. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure randomised trial—the Losartan Heart Failure Survival Study ELITE II. Lancet 2000 355 1582-1587. 

Doval HC, Nul DR, Grancelli HO, Perrone SV Bortman GR, Curiel R, Randomised trial of low-dose amiodarone in severe congestive heart failure, Grupo de Estudio de la Sobrevida en la Insuficiencia Cardiaca en Argentina (GESICA). Lancet 1994 344 493-498. 

The RALES trial randomised 1663 patients with stable heart failure to either placebo or spironolactone (New England Journal of Medicine 1999 341 709). All patients were maintained on their optimised therapy that included ACE inhibitors. After 2 years of follow-up the trial was terminated prematurely due to a 30% reduction of mortality in the spironolactone treated patients both progressive pump failure and sudden death were significanly reduced. Gynaecomastia or breast discomfort occurred in 10% of treated patients (1% in controls), but significant h) erkalemia occurred in surprisingly few patients. RALES was not adequately powered to decide whether the action of spironolactone is additive to that of a p-blocker. 

Northridge D 1996 Frusemide or nitrates for acute heart failure [see comments] Lancet 347 667-668 Peters N S et al 2002 Atrial fibrillation strategies to control, combat and cure. Lancet 359 593-603 Pitt B et al 2000 Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure randomised trial — the Losartan Heart Failure Survival Study ELITE II. [see comments] Lancet 355 1582-1587 Podrid P J 1999 Redefining the role of antiarrhythmic drugs. New England Journal of Medicine 340 1910-1912... 

The Franco-Belgium Collaborative NO Trial Group. Early compared with delayed inhaled nitric oxide in moderately hypoxaemic neonates with respiratory failure a randomised controlled trial. Lancet 1999 354(9184) 1066-71. 

Oral ibandronate has also been investigated in patients with metastatic bone disease. In 2 pooled Phase III studies, 564 patients with metastatic bone disease from breast cancer were randomised to receive 50 mg oral ibandronate or placebo once daily for up to 96 weeks [84]. Oral ibandronate significantly reduced the mean rate of new skeletal complications by almost 20% compared with placebo (P=0.004). The incidence of mild treatment-related upper gastrointestinal adverse events was slightly higher for oral ibandronate compared with the placebo group, whereas the renal adverse event rate was comparable between the 2 groups (ibandronate, 5.2% placebo, 4.7%) with no report of renal failure [84]. 

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