Placebo subject numbers

PLACE THE NUMBER OF PLACEBO SUBJECTS IN N2. select count(distinct subjid) format = 3. into n2 from treat where trtcd = 0 ... 

Subject number Weight after placebo (kg) Weight after active (kg) Change in weight (active-placebo) (kg)... 

I once helped to design such a trial involving four doses and 36 subjects for which the physicians involved proposed having a 6 3 split between active and placebo subjects for each dose level. 1 pointed out that for four fewer subjects altogether, a 4 4 split would be just as efficient. For example, for the purpose of comparing active with placebo, the variance would be proportional to (1/4-F 1/4) = 1/2 and thus the same as for the proposed design where it would be proportional to (1/6-1-1/3) which is also equal to 1/2. Of course, a 54 split would be more efficient and would use exactly the same number of subjects as originally proposed. 

The current evidence suggests that there might be some beneficial effects on postmenopausal symptoms, but it is not possible to be more categorical at present given the conflicting observations in the limited number of studies undertaken and the possibility that placebo effect may explain the changes noted in the incidence of subjective symptoms. 

ECASS-II was designed to test a lower dose of rt-PA (0.9 mg/kg) during the same 0-6-hours time period after stroke onset, using similar inclusion criteria as in ECASS-I. ° The primary endpoint was the proportion with a favorable outcome on the mRS scale (defined as a score of 0 or 1). There was no difference in this outcome between rt-PA-treated and placebo controls (40% vs. 37%, p = 0.28). A separate analysis of the 158 subjects enrolled within 3 hours of stroke onset also showed no difference in the proportion with a favorable outcome (42% vs. 38%, p = 0.63) this result, however, must be treated with caution because in ECASS-II there was a substantially lower number of patients treated within 3 hours of stroke onset, compared to the 1995 NINDS rt-PA study. Parenchymal hematoma on post-treatment CT was seen in 12% of rt-PA-treated and 3% of placebo patients (p < 0.001). The 90-day mortality rate was 11 % for the rt-PA group and 11 % for the placebo group (p = 0.54). Protocol violations were much less frequent in ECASS-II compared to ECASS-I (9% vs. 18%), probably because of standardized training in CT interpretation at the study sites. 

Often there is a desire to compare responses to multiple treatments rather than simply evaluate active against a placebo control. For instance, it may be useful to evaluate several doses or to assess a product against another marketed product. Increasing the number of treatments will increase the sample size required overall, but will also increase the number of subjects required per treatment arm because the number of statistical comparisons is larger. If all between-group comparisons are to be made, the number of statistical tests increases dramatically as the number of treatment arms increases. With two groups, only one comparison is possible. With three groups, the number... 

For some conditions, a large placebo effect can be anticipated. For example, studies of hormone replacement therapies for hot flashes in postmenopausal women consistently show a 50% decline from baseline in the number of daily hot flashes in the placebo group. Therefore, in order to show significance, an active treatment must produce an effect that is substantially larger than 50%. A marked placebo response is commonly observed with any condition that has a subjective component, such as chronic pain (e.g. arthritis), episodic pain (e.g. headaches), psychological states (e.g. anxiety), and certain physiologic measurements (e.g. blood pressure). 

The larger the benefit, the smaller the number of subjects required to show statistical significance. For example, if a herbal supplement is expected to produce a 5% lowering of the blood cholesterol level vs placebo, this will require many more subjects than a study evaluating the effects of a drug that is expected to produce a 50% reduction vs placebo. 

The article that follows is a controversial one. It reaches a controversial conclusion - that much of the therapeutic benefit of antidepressant medications actually derives from placebo responding. The article reaches this conclusion by utilizing a controversial statistical approach - meta-analysis. And it employs meta-analysis controversially - by meta-analysing studies that are very heterogeneous in subject selection criteria, treatments employed, and statistical methods used. Nonetheless, we have chosen to publish the article. We have done so because a number of the colleagues who originally reviewed the manuscript believed it had considerable merit, even while they recognized the clearly contentious conclusions it... 

The first influential verification of the power of placebo to produce real effects was reported in 1950 by Stewart Wolf, a physician and medical researcher at Cornell University.9 In his seminal article on the pharmacology of placebos , Wolf described a number of experimental demonstrations of the ability of a placebo to reverse the effects of an active medication. In each case the reversal was brought about by misinforming the subject about the nature of the drug being administered, and in each... 

A number of studies have investigated the potential of melatonin to alleviate the symptoms of jet lag. Melatonin has been found to be effective in 11 placebo-controlled studies in reducing the subjective symptoms of jet lag such as sleepiness and impaired alertness (Arendt 2005). The most severe health effects of jet lag occur following eastbound flights, since this requires a phase advancement of the biological clock. In a recent study, phase advancement after melatonin administration (using 3 mg doses just before bedtime) occurred in all 11... 

Reminiscent of the trend with laboratory studies, most (33 out of 43 cited above) uncontrolled clinical trials with either healthy volunteers or cardiovascular patients suggest that oral and intravenous NO donors at therapeutic doses acutely inhibit platelet activation in vivo (vide supra). Aside from their lack of long-term dosing and a placebo control group, several considerations restrict the predictive clinical value of these uncontrolled clinical studies limited numbers of subjects nonuniform criteria for subject entry and treatment outside of the trial induction of adrenaline or... 

First, the most recent (October, 2000) revision of the Declaration of Helsinki (World Medical Association, 2000) calls for discontinuing the use of placebo controlled trials in patients. While this is not currently binding on U.S. trials (FDA has specifically said that they will not mirror this as a requirement), and is intended to protect the health of participating patient subjects by precluding having some denied existing efficacious treatments (which would be the effect in most—but not all—cases), it will also likely cause the numbers of subjects required in a trial to increase. This will further stretch the economic aspects of limitations on the power of trials to assess potential drug safety in what will be the intended patient population. Trials are already very expensive each additional subject enrolled costs 15,000 or more in a Phase 11 or 111 trial. 

Randomized Crossover Design Subjects are divided into placebo and active groups. After some time these two groups crossover the initial placebo group now becoming the active group and vice versa. There may be a washout period before the crossover to enable the effect of the placebo and active to wash out. This method requires a smaller number of subjects and is useful in cases for studying rare or more stable illnesses. 

If subjects are to receive more than one dose level of active drug, there are a number of ways in which subjects can be allocated to active drug (A) or placebo (P) but essentially they fall into two approaches. 

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