Blinding sample size

Phase III is the confirmatory stage and major adaptation outside of pre-planned interim analyses and blinded sample size re-evaluation could potentially undermine the confirmatory nature of the trial. 

For a more realistic sample size than that in Example 7.7, one that contains 1.00 mol CO, corresponding to 6.02 x 1023 CO molecules, each of which could be oriented in either of two ways, there are 2602x10 (an astronomically large number) different microstates, and a chance of only 1 in 2< 02x l0" of drawing a given microstate in a blind selection. We can expect the entropy of the solid to be high and calculate that... 

A randomized, double-blind, placebo-controlled trial evaluating the use of a monophasic OC containing 30 meg ethinyl estradiol and 3 mg drospirenone, a progesterone with anti-androgenic effects, showed improvement in the treatment arm compared with placebo.31 In particular, appetite, food cravings, and acne improved. However, active treatment was not associated with a statistically significant improvement in the overall outcome measure, the Calendar of Premenstrual Experiences (COPE) scale, perhaps because of the small sample size (n = 82). 

No definitive conclusions can be drawn concerning a possible role of rifaximin in preventing major complications of diverticular disease. Double-blind placebo-controlled trials with an adequate sample size are needed. However, such trials are difficult to perform considering the requirement of a large number of patients. Assuming a baseline risk of complications of diverticular disease of 5% per year [2], a randomized controlled trial able to detect a 50% risk reduction in complications should include 1,600 patients per treatment group considering a power of 80% (1 - (3) and an a error of 5%. 

One algorithm for blindly approximating physical states has already been proposed [36], although the method requires the number of states to be input. In work to be reported soon, Zhang and Zuckerman developed a simple procedure for approximating physical states that does not require input of the number of states. In several systems, moreover, it was found that sample-size estimation is relatively insensitive to the precise state definitions (providing they are reasonably physical, in terms of the timescale discussion above). The authors are therefore optimistic that a "benchmark" blind, automated method for sample-size characterization will be available before long. 

In tong term trials there will usually be an opportunity to check the assumptions which underlay the original design and sample size calculations. This may be particularly important if the trial specifications have been made on preliminary and/or uncertain information. An interim check conducted on the blinded data may reveal that overall response variances, event rates or survival experience are not as anticipated. A revised sample size may then be calculated using suitably modified assumptions... ... 

Generally speaking these sample size considerations are independent of any formal interim comparisons of the treatments, be they efficacy or futility. Given the need to maintain blinding it is also advisable not to involve the DMC in these re-evaluations their potential knowledge of the unfolding data in an unblinded way could well influence their view on a change in the sample size - they know too much ... 

This document has set down some initial thoughts from a regulatory point of view about the issues involved in allowing the design of a clinical trial to be adapted as the trial progresses. Modification of the sample size based on blinded data and stopping for overwhelming efficacy or futility are forms of adaptation that are already well accepted, but this Reflection Paper considers other possibilities that are more controversial. 

In the Zito et al. study (2000), antidepressants were the second most commonly prescribed psychotropic medication. There are a total of 10 studies or case reports in the literature examining antidepressant use in preschool children (Table 49.4). None of the 10 studies are randomized, double-blind, or placebo-controlled trials. The ten uncontrolled studies looked at a total of 37 preschool children. Six of the studies looked at a total of 29 preschoolers with autism or childhood schizophrenia (Campbell et ah, 1971a Petti and Campbell, 1975 Holttum et ah, 1994 Sanchez et ah, 1996 DeLong et ah, 1998 Hollander et ah, 2000). While these six studies are difficult to compare, given the small sample sizes and the different treatment medications, these open-label studies suggest that clomipramine, venlafaxine, and fluoxetine may be helpful to reduce some psychiatric symptoms found in autistic... 

In view of the limited sample size of PoC trials, minimization of bias and control of unspecific effects are essential double-blind, randomized, placebo-controlled studies are the rule. 

It is important to distinguish between acute (e.g., 1 day) and longer term treatment with a BZD. Most of the literature addressing this issue consists of anecdotal reports, retrospective chart reviews, and uncontrolled studies in small patient samples, plus a small number of controlled trials for short-term acute BZD therapy. To our knowledge, at least 12 studies (including more than 450 patients) have evaluated the efficacy of adjunctive BZDs in nonresponsive schizophrenics (Table 5-23). Two of three open studies showed positive results, as did two controlled, single-blind studies ( 343, 344, 345, 346 and 347). In seven double-blind, crossover studies (six with placebo controls), the results are more contradictory, in that five showed no advantage to an adjunctive BZD, and one of the two positive studies had a small sample size (188, 189, 348, 349, 350 and 351). 

Trazodone Preliminary data suggest that trazodone may be effective in reducing the three primary symptom clusters of PTSD. These findings, however, need to be confirmed in a double-blind, placebo-controlled, larger sample size study ( 282). 

Design, Treatment and Sample Size Single-center, single-dose, double-blind, randomized, two-way crossover design 20 pediatric type I diabetic subjects (10 per age class) of either gender. The 2 age classes were build by children aged between 5 and 11 years and adolescents aged between 12 and 17. 

Most recently, in a small double blind trial (Lane et al., 2008), sarcosine showed efficacy as monotherapy in acutely decompensated patients. Despite the small sample size, the monotherapy study represents a critical evolution of the NMDA-based therapeutic approach, which had up until then been limited to addon studies. In the study, no true placebo was used, although a lower dose of sarcosine was used as partial control and in order to evaluate the dose-dependence of findings. Obviously, more extensive clinical trials, as well as the introduction of high affinity, selective GLYT1 inhibitor compounds, are needed. 

In addition to being accurate and valid, clinical findings must also be relevant to the anticipated therapeutic effect. They must be sufficient to prove that the efficacy of the study drug is comparable to, or perhaps greater than, a well-chosen and well-blinded control, and that its safety has been similarly profiled. Obviously, if the study design and protocol, including such basics as the study sample size, are not adequate for this complex task, the data collection... 

The statistician should note when interpreting the statistical analysis that the failure to find significant differences in the final data might be attributable to the quality of that data as recorded, perhaps to the quality of the study design or to insufficient sample size, therefore insufficient statistical power. Bias in clinical findings, particularly in nonblinded or poorly blinded studies, is one possible cause. 

In a 12-week, double-blind, randomized, placebo-controlled study in 40 patients with treatment-resistant schizophrenia (funded by Johnson Johnson Pharmaceutical Research Development), the addition of risperidone to clozapine improved overall symptoms and positive and negative symptoms (49). The adverse events profile of clozapine + risperidone was similar to that of clozapine + placebo. Clozapine + risperidone did not cause additional weight gain, agranulocytosis, or seizures compared with clozapine + placebo. All the patients completed 12 weeks of treatment however, the small sample size precluded definitive conclusions. 

Clonazepam is widely used for the treatment of sleep disturbances related to post-traumatic stress disorder, despite very limited published data supporting its use for this indication. In a randomized, single-blind, placebo-controlled, crossover trial of clonazepam 1 mg at bedtime for 1 week followed by 2 mg at bedtime for 1 week in six patients with combat-related post-traumatic stress disorder there were no statistically significant differences between clonazepam and placebo (4). Adverse effects of clonazepam were generally mild and essentially indiscernible from those attributed to placebo. Only one patient elected to continue taking clonazepam at the end of the trial. The small sample size was a significant limitation of the study. 

Selegiline may have anti-oxidant and anti-apoptotic properties in addition to inhibiting MAO, and has been reported to increase SOD activity in the basal ganglia of rats (Knoll, 1989). There have been several duals of selegiline 10mg per day in patients with ALS a randomized, placebo controlled, double blind trial (Lange et al., 1998), and a placebo-con trolled crossover trial (Mitchell et al., 1995). Neither showed improvement in functional or subjective rating scales, but both trials were underpowered due to insufficient sample size and so may be considered inconclusive. 

In a double-blind, randomized comparison of subUngual buprenorphine tablets with oral methadone in a 6-week trial in 58 patients using a flexible dosing procedure the retention rate was significantly better in those using methadone (90 versus 50%) (22). Those who completed the study had a similar number of opioid-positive urine samples, with a mean stabilization dose of 11 mg/day of buprenorphine and 70 mg/day of methadone. This study had several limitations 6 weeks is too short a period to determine any intermediate or long-term treatment outcomes, the sample size was too small, and the comparison of non-equivalent doses makes interpretation difficult. 

Suggestions for improved gastrointestinal safety of COX-2-selective inhibitors have come from two studies, which addressed the problem of sample size by pooling published and unpublished randomized, double-blind trials of varying design and duration, comparing cele-coxib, rofecoxib, non-selective NSAIDs (diclofenac, ibu-profen, nabumetone), and placebo in patients with osteoarthritis and/or rheumatoid arthritis. 

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