Dose ranging studies

The discussion so far in this section has assumed that the treatment groups are unordered. There are, however, situations where these multiple treatment groups correspond to placebo and then increasing dose levels of a drug. It could still be in these circumstances that we are looking to compare each dose level with placebo in order to identify, for example, the minimum effective dose and again we are back to the pairwise comparisons. 

There will be, however, some circumstances where we are just interested in trends if we increase the dose does the mean response increase  

For continuous data there is a procedure within the one-way analysis of variance methodology that is able to focus on this we would be looking for a trend across the treatment groups. 

For binary, categorical and ordinal data there is also an approach which is a further form of the Mantel-Haenszel chi-square test. You will recall that the MH test is used for ordinal responses comparing two treatments. Well, this procedure generalises to allow ordering across the treatment groups in addition, for each of 

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Anton RF, Pettinati H, Zweben A, et al A multi-site dose ranging study of nalmefene in the treatment of alcohol dependence. J Clin Psychopharmacol 24 421 28, 2004 Aragon CM, Stotland LM, Amit Z Studies on ethanol-brain catalase interaction evidence for central ethanol oxidation. Alcohol Clin Exp Res 15 165-169, 1991 Arizzi MN, Correa M, Betz AJ, et al Behavioral effects of intraventricular injections of low doses of ethanol, acetaldehyde, and acetate in rats studies with low and high rate operant schedules. Behav Brain Res 147 203—210, 2003 Azrin NH, Sisson RW, Meyers R, et al Alcoholism treatment by disulfiram and community reinforcement therapy. J Behav Ther Exp Psychiatry 13 105—112, 1982 Babor TF, Kranzler HR, Lauerman RL Social drinking as a health and psychosocial risk factor Anstie s limit revisited, in Recent Developments in Alcoholism, Vol 5. Edited by Galanter M. New York, Plenum, 1987, pp 373 02... 

Loo, H., Hale, A. Dhaenen, H. (2002). Determination of the dose of agomelatine, a melatoninergic agonist and selective 5-HT2C antagonist, in the treatment of major depressive disorder a placebo-controlled dose range study. Int. Clin. PsychopharmacoL 17, 239-47. 

Eriksson, B. I., Arfwidsson, A. C., Frison, L., Eriksson, U. G., Bylock, A. et al, A dose-ranging study of the oral direct thrombin inhibitor,... 

Mortimer K, Brown A, Feary J, et al Dose-ranging study for trials of therapeutic infection with Necator ameri-canus in humans. Am J Trop Med Hyg 2006 75 914-920. 

Nabi has successfully completed several phase II studies for NicVAX. The results from a phase Ilb dose-ranging study in 301 heavy smokers showed that a significantly greater number of vaccinated participants met abstinence endpoints compared to placebo. Furthermore, vaccinated participants who successfully achieved abstinence were shown to have a higher level of antibody response than those vaccinated participants who did not achieve abstinence (Nabi Biopharmaceuticals 2007). Nabi is expected to start phase III trials this year. 

Krause DS, Reinhardt J, Vazquez JA, Reboli A, Goldstein BP, Wible M, Henkel T. (2004) Phase 2, randomized, dose-ranging study evaluating the safety and efficacy of anidulafungin in invasive candidiasis and candidemia. Antimicrob Agents Chemother 48 2021-2024. 

HIV treatment In combination with other antiretroviral agents for the treatment of HIV infection. This indication is based on analyses of plasma HIV RNA levels and CD4 cell counts in a controlled study of lopinavir/ritonavir combination of 24 weeks duration and in smaller uncontrolled dose-ranging studies of 72 weeks duration. At present, there are no results from controlled trials evaluating the effect on clinical progression of HIV. 

Spencer, X, Biederman, J., Heiligenstein, J., Wilens, X, Paries, D., Prince, J., Earaone, S.V., Rea, J., Witcher, J., and Zeras, S. (2001) An open-label, dose-ranging study of atomoxetine in children with attention deficit hyperactivity disorder. J Child Adolesc Psychopharmacol 11 ... 

Bradwejn J, Koszycki D, Bourin M Dose ranging study of the effect of CCK-4 in healthy volunteers. J Psychiatry Neurosci 16 260-264, 1991a... 

Spencer T, Biederman J, Heiligenstein J, et al An open-label, dose-ranging study of atomoxetine in children with attention deficit hyperactivity disorder. J Child Adolesc Psychopharmacol 11 251-265, 2001... 

Clinical trials indicate that quetiapine has a low propensity to evoke EPS ( 128, 476). Treatment with quetiapine did not induce EPS in the dose range studied, as determined by the following ... 

Poon T, Nelson P, Shen L, Mihm M, Taylor K, Fineman M, Kim D. Exenatide improves glycemic control and reduces body weight in subjects with type 2 diabetes a dose-ranging study. Diabetes Technol Ther 2005 7 467-72. 

Gribble FM, Manley SE, Levy JC. Randomized dose ranging study of the reduction of fasting and postprandial glucose in type 2 diabetes by nateglinide (A-4166). Diabetes Care 2001 24(7) 1221-5. 

Phase II (safety and dose ranging studies) 50 per cent chance of success. 

Therapeutic window identified in dose-ranging studies... 

The reduction was dose-related within the dose range studied (0.1-10 g/kg) (Thunberg et al. 

Knowles, M. R., Noone, P. G., Hohneker, K., Johnson, L. G., Boucher, R. C., Efthimiou, J., Crawford, C., Brown, R., Schwartzbach, C. and Pearlman, R. (1998). A double-blind, placebo controlled, dose ranging study to evaluate the safety and biological efficacy of the lipid-DNA complex... 

Eriksson Bl, Arfwidsson AC, Frison L, et al. A dose-ranging study ofthe oral direct thrombin inhibitor, ximelagatran, and its subcutaneous form, melagatran, compared with dalteparin in the prophylaxis of thromboembolism after hip or knee replacement METHRO I, MEIagatran for THRombin inhibition in Orthopaedic surgery. Thromb Haemost 2002 87 231-237. 

In particular, high-dose data usually cannot identify a threshold. A threshold is a dose or exposure below which there is no effect. It is often assumed that there is no threshold for an end point, like a gene mutation, that may involve one molecule of the toxicant and one target molecule in such a case, the dose-response relationship would be linear at low doses. If the observed relationship is linear over the dose range studied and if the fitted line is extrapolated to no effect (or the background frequency of effects) at zero dose, linear kinetics with no threshold are likely. But data are usually not clear. Even such a large carcinogenesis study as the EDqi study conducted by... 

In order to decide to enter Phase III or not, all available knowledge has to be used to predict the clinical outcome (efficacy and safety) in Phase III. Phase III clinical trials differ in several aspects from Phase II trials, which makes this step not always easy. These aspects are basically (1) the patient population, (2) the dose range studied, and (3) the primary endpoint. 

In a double-blind, placebo-controlled, dose-ranging study in 35 antiretroviral-naive HIV-infected patients (Protocol 004), subjects were randomized to receive placebo or one of four raltegravir doses (100, 200, 400, or 600 mg) twice daily over 10 days. Although dose proportionality was not observed (possibly due to intersubject variability and the small number of patients), the pharmacokinetic data gathered in this study supported the selection of a 400-mg dose for raltegravir.27... 

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