Sequenced Treatment trial

Rush, A. J., Fava, M., Wisniewski, S. R. et al. (2004). Sequenced treatment alternatives to relieve depression (STAR D) rationale and design. Controlled Clinical Trials, 25(1), 119-42. 

A single-center, open-label, randomized, balanced, singledose, two-treatment (fed versus fasted), two-period crossover design. In one trial period subjects were dosed after fasting (= fasted trial period), and in the other trial period subjects were dosed after consuming a high fat breakfast (= fed trial period). Subjects were randomized to the sequence of trial periods. The washout period between trial periods was at least 5 days which approximated to > 10 Drug XYZ apparent terminal half-lives. 

There are two main types of clinical trial design, parallel and cross-over. In a parallel study, subjects are assigned to one of two or more treatments, e.g. active and placebo, and proceed through the trial concurrently. In a cross-over design, subjects act as their own controls, undergoing two or more treatments in sequence (see Fig. 12.1). 

Crossover design A clinical trial design in which patients receive, in sequence, the treatment (or the control), and then after a specified time, receive the opposite arm of the trial. This allows patients to serve as their own controls. Randomization should be... 

An alternative system, which effectively results in the introduction of antisense oligonucleotides into the cell, entails application of gene therapy. In this case, a gene, which when transcribed yields (antisense) mRNA of appropriate nucleotide sequence, is introduced into the cell by a retroviral or other appropriate vector. This approach, as applied to the treatment of cancer and AIDS, is being appraised in a number of trials. 

In this context, each patient would be receiving each of the multiple treatments. In the cross-over trial with three treatments this would likely be a three-period, three-treatment design and patients would be randomised to one of the six sequences ABC, ACB, BAC, BCA, CAB or CBA. Although there are again ways of asking a simultaneous question relating to the equality of the three treatment means through an analysis of variance approach this is unlikely to be of particular relevance questions of real interest will concern pairwise comparisons. 

Faedda GL, Baldessarini RJ, Tohen M, et al Episode sequence in bipolar disorder and response to lithium treatment. Am J Psychiatry 148 1237-1239, 1991 Falkenburg T, Mohammed AK, Henriksson B, et al Increased expression of brain-derived neurotrophic factor mRNA in rat hippocampus is associated with improved spatial memory and enriched environment. Neurosci Lett 138 153-156, 1992 Fallon BA, Campeas R, Schneier FR, et al Open trial of intravenous clomipramine in five treatment-refractory patients with obsessive-compulsive disorder. J Neuropsychiatry Clin Neurosci 4 70-75, 1992... 

This is an extension of the crossover design that applies in situations where more than two treatment conditions are being evaluated. Each subject receives each treatment successively but in a different sequence. This design can be used in the case of single-dose experimental trials, such as studies of cognitive function, psychomotor performance, psyehophysiological responses, etc. in healthy volunteers (Chapter 3) but also in therapeutic short-term trials of hypnotics or anxiolytics. 

Clinical trials have demonstrated excellent efficacy with recombinant human factor VIII concentrates available as Recombinate and Kogenate. These recombinant factor VIII products are purified from the cell culture of plasmids, not viral DNA-transfected hamster cells and therefore do not express viral sequences. The addition of human serum albumin for stabilization, constitutes the sole possible source for human viral contamination. More recently recombinant factor IX has been genetically engineered by insertion of the human factor IX gene into a Chinese hamster ovary cell line. It has been proved to be safe and effective in the treatment of patients with hemophilia B. 

ABT-594 is reported to be in clinical trials for the treatment of neuropathic pain (Thatte, 2000 Sorbero et al. 2001). Its precursor (f )-N-Boc-azetidin-2-yl-methanol is accessible in a short sequence starting from commercially available D-aspartic acid dibenzyl ester. The synthesis is concluded by Mitsunobu coupling with 6-chloropyridin-3-ol and subsequent acidic deprotection. On a larger scale the primary alcohol is activated as a mesylate prior to coupling with 6-chloropyridin-3-ol in the presence of potassium hydroxide, so that Mitsunobu conditions can be avoided (Meyer et al., 2000). 

The majority of the proteins in clinical trials in August 1991 were monoclonal antibodies for treatment of sepsis or neoplasia (see Immunotherapeutic agents). Monoclonal antibodies are derived in most cases from mouse cell lines. This leads to the problem that the antibodies are recognized as foreign by the human immune system. Research efforts are directed toward humanizing antibodies so that these molecules can escape immune surveillance, for example, by the systematic replacement of murine-specific peptide sequences with human homologues while still maintaining the... 

In a randomized trial in 74 patients with chronic hepatitis C treated with interferon alfa-2b and ribavirin, plus placebo or amantadine, two developed glutamic acid decarboxylase (GAD) autoantibodies, but none developed IA-2 or insulin autoantibodies (543). One had an increased titer of GAD autoantibodies during a first sequence of interferon alfa monotherapy, then a further rise during subsequent combination therapy, and finally developed diabetes mellitus after 5 months of treatment. The authors suggested that repetitive treatment with interferon alfa could increase the risk of type 1 diabetes in patients previously positive for islet antibodies. 

Randomization is also an important idea in the design of experiments. It has to do with the random sequence of doing trials so as to annul the influence of systematic factors, which are difficult to stabilize and control. In this way one of the main concepts of classical experiment, having to do with the necessity of fixing disturbance factors, is disrupted. Randomization is the means used to eliminate any bias in the experimental units and/or treatment of combinations-trials. If the data are random it is safe to assume that they are independently distributed. Errors associated with experimental units, which are adjacent in time or space will tend to be correlated, thus violating the assumption of independence. Randomization helps to make this correlation as small as possible so that the analyses can be carried out as though the assumption of independence were true. 

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