Dose-finding trials

Moreland, L. W., Margolies, G., Heck, L. W., Jr. et al. (1996). Recombinant soluble tumor necrosis factor receptor (p80) fusion protein Toxicity and dose finding trial in refractory rheumatoid arthritis. J Rheumatol 23, 1849-1855. 

Preliminary studies over 3 months in groups of 10 animals each are an essential requirement in Japan. Since adequate dose levels for such a long-term study are difficult to define beforehand, short dose-finding trials may be be useful for other countries, too. 

Dodel R, Rominger A, Bartenstein P, Barkhof F, Blennow K, Forster S et al (2013) Intravenous immunoglobulin for treatment of mild-to-moderate Alzheimer s disease A phase 2, randomised, double-blind, placebo-controlled, dose-finding trial. Lancet Neurol 12 233-243... 

Parallel assay. A dose-finding trial in which the potency of a new treatment is established by comparing its dose-response to the dose-response of a standard treatment. 

White J, Bell J, Saunders JB, Williamson P, Makowska M, Farquharson A, Beebe KL. Open-label dose-finding trial of buprenorphine implants (Probuphine ) for treatment of heroin dependence. Drug Alcohol Depend 2009 103 37-43. 

Kumar, N.B., Kang, L., Pow-Sang, J., Xu, P., Allen, K., Riccardi, D., Besterman-Dahan, K., and Krischer, IP. 2010. Results of a randomized phase I dose-finding trial of several doses of isoflavones in men with localized prostate cancer administration prior to radical prostatectomy. 

Engel WK. (2009) Intravenous immunoglobulin in relapsing-remittin multiple sclerosis a dose-finding trial. Neurology 73, 1077-1078. 

Typically, later phase trials tend to have the confirmatory elements while the earlier phase studies proof of concept, dose-finding etc. are viewed as exploratory. Indeed an alternative word for confirmatory is pivotal. It is the confirmatory elements of our trials that provide the pivotal information from a regulatory perspective. 

Proof-of-efficacy trials these studies should provide, within a limited time frame and with a low-cost program, sufficient information for a go/no-go decision concerning efficacy and safety aspects of a new compound. The traditional approaches are Phase lib trials based on placebo-controlled dose-finding designs. These studies need relatively high power, which means the inclusion of several dozen to several hundred patients. 

Four clinical phase 1 studies involving 72 healthy elderly subjects have been performed and have showed that administration of ZT-1 in humans seems to be safe and well tolerated. The incidence of possibly drug-related adverse events, in particular nervous system and gastrointestinal symptoms, was similar to placebo for doses up to 1.5 mg. An international multicenter phase II trial for dose finding and efficacy assessment, in mild-to-moderate AD patients, is underway in 28 hospitals in Europe. 

TABLE 18.2 Comparison of Recommended Doses for Antihypeitensive Agents Based on Initial Dose-Finding Clinical Trials and Subsequent Experience in Randomized Clinical Trials and Clinical Practice ... 

Tlie clinical utility of another first-generation, non-nitrogen-containing bisphosphonate, tiludronate, has been limited because of concern over renal adverse effects observed in early trials. In a dose-finding study for the treatment of HCM, 19 patients received i.v. drug followed by oral maintenance therapy [70]. Three patients had elevated serum creatinine levels after i.v. drug administration of 4.5 or 6.0 mg/kg, 1 of whom developed acute renal insufficiency and subsequently died, most probably due to tiludronate, although renal infection and allopurinol therapy could have played a contributory role. 

Phase II trials, termed dose finding studies, in a table listing the length of the study period and the number of subjects. Results of the Crixivan trials were compared to other treatments, especially AZT when taken alone. Phase III trials, generally considered key to determining efficacy, are described as confirmatory trials, since Crixivan s early success had put it on an accelerated track. 

In an initial confirmation of the preclinical findings, a phase II clinical trial using 10-40 mg of MDL 100907 per day for 6 weeks showed improved Parkinson rating scale (BPRS) scores relative to placebo and no EPS liability (665). A larger phase III trial showed some minor improvement in positive symptoms at the 10-mg/day dose, but this effect disappeared at the 20-mg/day dose, compared with placebo. Functional PET scans of selected patients in the trial showed minor metabolic changes in the frontal cortex at the 10 but not 20 mg dose. Clinical trials of MDL100907 have been halted, presumably because of limited efficacy (666). Between the findings with ritan-... 

I Dose-finding studies of new medications to determine acute toxicity. Healthy subjects or patients. These studies warrant close REB review with continuous monitoring independent of the trial sponsor. This is especially important as more of these trials include patients refractory to standard therapy, and with the increasing number of new medications. Unexpected adverse events tu e a major concern. 

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