Clinical trials measuring treatment effects

BP effects In clinical trials, duloxetine treatment was associated with mean increases in BP, averaging 2 mm Hg systolic and 0.5 mm Hg diastolic and an increase in the incidence of at least 1 measurement of systolic BP over 140 mm Hg compared with placebo. Measure BP prior to initiating treatment and periodically throughout treatment. 

FIGURE 10.24 Of the 16 p-blockers that have been studied in clinical trials for treatment of congestive heart failure, 3 have been shown to have measurably favorable effects, with carvedilol emerging as the most efficacious. Carvedilol has a number of activities in addition to p-adrenoceptor affinity that may make it efficacious in the treatment of congestive heart failure. Data from [62],... 

The few clinical trials on the effectiveness of avoidance measures have been inconclusive. These measures are intended to be a part of a comprehensive treatment strategy that will likely inclnde pharmacotherapy and in selected cases, immnnotherapy. 

Although increases in bone mineral density have been reported at other sites, most of the clinically significant fractures occur in the hip or spine, and these sites have become clinically important measures in the trials. These increases in bone mineral density are an important marker of treatment effects and are related to the benefits found in larger trials of decreased fracture risk. 

To date, three pharmaceutical companies have entered clinical trials with PHD inhibitors for the treatment of anemia with the most advanced being FG-2216. In clinical studies, compound 2 (likely FG-2216) showed a dose- and time-dependent elevation of plasma erythropoietin after oral administration [66]. Healthy volunteers were orally administered various doses of compound 2 and serum erythropoietin (EPO) concentrations were measured at various times. Compound 2 increased serum EPO levels in a dose-dependent manner and, following administration of the 20 mg/kg dose, a 5-fold increase of EPO levels was observed after 12 h. In the same patent application, the effect of 2 on anemic predialysis patients with no previous rh-EPO exposure was also disclosed. Patients were treated with 2 three times/week for 4 weeks (no dose reported) and the hemoglobin levels were assessed on day 42. The patients who received treatment showed a mean increase in hemoglobin of 1.9 g/dL from baseline values, whereas subjects who received placebo showed a mean decrease of 0.35 g/dL from baseline levels. These data suggest for the first time that an oral PHD inhibitor could be effective for the treatment of anemia. 

The aim of any clinical trial is to have low risk of Type I and II errors and sufficient power to detect a difference between treatments, if it exists. Of the three factors in determining sample size, the power (probability of detecting a true difference) is arbitrarily chosen. The magnitude of the drug s effect can be estimated with more or less accuracy from previous experience with drugs of the same or similar action, and the variability of the measurements is often known from published experiments on the primary endpoint, with or without the drug. These data will, however, not be available for novel substances in a new class and frequently the sample size in the early phase of development has to be chosen on an arbitrary basis. 

Laupacis et al. introduced the number needed to treat (NNT) into the medical literature" as an easily imderstood and useful measure of treatment effect for clinical trials in which the main outcome variable is binary. It has been argued that the NNT is more easily... 

In projecting results of short-term trials over patients lifetimes, it is typical to present at least two of the many potential projections of lifetime treatment benefit. A one-time effect model assumes that the clinical benefit observed in the trial is the only clinical benefit received by patients. Under this model, after the trial has ended, the conditional probability of disease progression for patients is the same in both arms of the trial. Given that it is unlikely that a therapy will lose all benefits as soon as one stops measuring them, this projection method generally is pessimistic compared to the actual outcome. A continuous-benefit effect model assumes that the clinical benefit observed in the trial is continued throughout the patients lifetimes. Under this model, the conditional probability of disease progression for treatment and control patients continues at the same rate as that measured in the clinical trial. In contrast to the one-time model, this projection of treatment benefit most likely is optimistic compared to the treatment outcome. 

In clinical practice, nitrates are used on a large scale in the treatment of ischaemic heart disease, in particular stable angina. Although very effective as a symptomatic measure, it remains unclear so far whether the prognosis of patients with stable angina is improved by nitrate treatment. Clinical trials addressing this question are ungoing. 

The drug is slowly cleared from vitreous with a half-life of approximately 55 hours in humans and is subsequently cleared from the retina. Measurable concentrations of drug are not detected in the systemic circulation following intravitreal administration. Immediate therapy of CMV retinitis with fomivirsen was more effective in delaying progression than deferred treatment in a recent clinical trial. Concurrent systemic anti-CMV therapy is recommended to protect against extraocular and contralateral retinal CMV disease. Potential side effects include iritis and vitreitis as well as increased intraocular pressure and changes in vision. An interval of at least 2-4 weeks is recommended between cidofovir administration and use of fomivirsen because of the risk of ocular inflammation. 

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