Treatment withdrawal study designs

Sources of bias in this study design arise from the exposure of patients to lower doses first. Patients obligatorily must tolerate, and fail to respond to, lower doses before being exposed to higher doses. Any degree of treatment familiarization, tachyphylaxis, or patient withdrawal rate biases dose-... 

A higher percentage of patients would be expected to relapse in the crossover design for two reasons. First, a significant portion of the patients in the crossover study had, in fact, responded specifically to the drug treatment. After a period of stabilization, these patients were randomly reassigned to placebo and thus would be expected to relapse. Second, a basic problem in the crossover design is that withdrawal symptoms can mimic the recurrence of depressive symptoms. That is true for the SSRIs, particularly fluvoxamine and paroxetine, because of their relatively short half-lives. 

Despite these design flaws, many of the studies support the beneficial effects of tricyclic antidepressants in the treatment of depression associated with alcohol withdrawal. These benefits, however, do not exceed those of placebo after 3 weeks, and thus may have only limited application in actual clinical practice. 

In a study of oral famciclovir versus oral aciclovir, designed to demonstrate equivalence of efficacy of the two drugs in the treatment of mucocutaneous Herpes simplex infection in HIV-infected individuals, there was no difference in the incidence or nature of adverse effects in the two groups (1). None of the withdrawals from the trial was considered by the investigator to be related to the study medication. 

Naltrexone 50 mg/day has been used to relieve pruritus in cholestatic liver disease in five patients (7). Pruritus scores fell, but two patients developed severe nausea, vomiting, light-headedness, or tremor, requiring withdrawal of treatment. The reviewers commented that these reactions may or may not have been related to opioid withdrawal and that the trial had had several design limitations. They pointed out that one concern relating to the chronic use of high-dose naltrexone is an asymptomatic rise in serum transaminases, although the doses used in this study have not been reported to produce liver function abnormalities. 

Another difficult aspect in the design of open-label studies is how one assesses those patients who withdraw from the study. The reasons for withdrawal can be at least as varied as in double-blind studies (intolerability, administrative difficulties, coincidental emergent disease or concomitant therapies, etc.). However, in addition, in an open-label design, patients may develop an opinion on the superiority of one or other treatment for reasons that may or may not be explicit. If completion of a course of therapy is one end point of the study, then all withdrawals can be accounted treatment failures, and the statistical handling is fairly straightforward. However, if there is another end point, and if withdrawals are imbalanced between the treatment groups and unrelated to product intolerability, then the situation becomes a lot more clouded. Under these latter conditions, the entire trial may have to be abandoned when it becomes apparent that the trial design cannot answer the hypothesis under test one way or the other. 

Drug formulations Impaired digestion in cystic fibrosis affects about 90% of patients. As soon as pancreatic insufficiency is identified, enzyme supplementation is prescribed, even for breast fed infants. In a prospective, randomized study 40 infants and toddlers were treated with Creon for children, a formulation that contains smaller granules and is administered with a dosing spoon (5000 lipase units per scoop) and Creon 10 000 for 2 weeks each in a crossover design [113 ]. The former was superior in terms of parents preference, but equally effective with regard to fat absorption. Three patients who took Creon for children had treatment-related adverse events abdominal pain, constipation, vomiting, with one withdrawal) compared with one who took Creon 10 000 (severe diaper dermatitis/nappy rash). 

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