Controlled clinical trials最新文献

When estimating the treatment effect in a randomized controlled trial, it is common to have a continuous outcome which is also observed at baseline. These observations are often prone to measurement error, for example due to within-patient variability. Controversy exists in the literature about whether baseline measurement error should be adjusted for in this context. Computer simulations were used to compare the biases in the estimated treatment effect, with and without adjusting for measurement error, and for different levels of observed baseline imbalance. The impacts of sample size (30 per group and 300 per group) and reliability coefficient (0.6, 0.8 and 1) were also assessed. The results show that in randomized controlled trials, the ordinary least squares (OLS) estimator without adjusting for measurement error is unbiased. On the contrary, adjusting for measurement error leads to bias, especially when sample sizes are small and/or measurement error is large. The treatment effect adjusting for measurement error is on average overestimated when the baseline mean of the control group is larger than that of the treated group. It is underestimated when the control group has a smaller baseline mean.

The Early Treatment for Retinopathy of Prematurity (ETROP) study was a randomized, prospective multicenter trial comparing the safety and efficacy of earlier vs. conventionally timed ablation of the peripheral retina for the management of moderate to severe retinopathy of prematurity (ROP). Approximately 7000 infants with birth weights <1251 g were screened at 26 centers over a 2-year period to achieve the sample size of 401 consented infants for the randomized trial. In order to minimize treatment of eyes with ROP that were likely to undergo spontaneous regression of the disease, a risk analysis model, RM-ROP2, was used to select for inclusion in the randomized trial only prethreshold eyes that had a high risk of an adverse outcome. The primary outcome measure was grating visual acuity measured by Teller acuity card testing conducted by masked testers in eyes randomized to earlier treatment vs. eyes randomized to conventional management when infants were 9 months post-term. Results were categorized into favorable (≥1.85 cycles/degree) vs. unfavorable (<1.85 cycles/degree). The secondary outcome measure was retinal structure, assessed by ophthalmological examinations conducted at 6 and 9 months post-term. Here we describe a unique approach used in the ETROP study to select high-risk prethreshold ROP eyes for randomization and details about design of the study. Study results indicated that earlier intervention in selected high-risk prethreshold eyes results in improved vision in premature infants with ROP.

This paper presents a method for undertaking Phase II trials in which not all patients are considered equally likely to respond to treatment. In ovarian cancer, for example, it has been shown that response is less likely in patients who have failed the previous treatment after only a short interval compared to those who have a protracted failure-free interval [Gynecol. Oncol. 36 (1990) 207]. The method is analogous to those used in phase III trials which estimate relative rather than absolute effects; a constant odds ratio, for example, encompasses multiple relationships between response rates. Phase II trials commonly test the null hypothesis H₀: P≤p₀ against the alternate hypothesis H₁: P≥p₁, where the response rate p₁ is the minimum required level of efficacy and p₀ the highest level which would indicate that the treatment is of no further interest. This approach can be extended by using the arcsine transformation to allow p₀ and p₁ to vary between patients, thus for the ith patient p_0i=(sin c_i)² and the efficacy level is set to p_1i=(sin (c_i+b))². The value of the arcsine parameter b therefore determines efficacy and the test for efficacy in the trial then becomes a test of the null hypothesis H₀: B≤0 against the alternate hypothesis H₁: B≥b. The value of b is determined by considering representative values of p₀ and p₁ and setting b=(sin⁻¹√p₁−sin⁻¹√p₀); b is thus the constant arcsine difference (CAD) between p_0i and p_1i. The variance of B is 1/4n, which is independent of P, trial designs are therefore independent of P, implying that all patients for whom this difference is identical can be entered into the same trial. This paper considers single-stage and two-stage CAD Phase II trials.

Pediatric asthma remains an important public health concern as its prevalence and cost to the health care system is rising. In order to promote innovative research in asthma therapies, the National Heart, Lung and Blood Institute created the Childhood Asthma Research and Education Network in 1999. As its first study, the steering committee of the Childhood Asthma Research and Education Network designed a randomized clinical trial to determine if persistent asthma could be prevented in children at a high risk to develop the disease. This communication presents the design of its first clinical trial, the Prevention of Asthma in Kids (PEAK) trial and the organization of the Childhood Asthma Research and Education Network that developed and implemented this trial.

Studies of the natural history of asthma have shown that, in persistent asthma, the initial asthma-like symptoms and loss of lung function occur predominately during the first years of life. Therefore, in the Prevention of Asthma in Kids study, children 2 and 3 years old with a positive asthma predictive index were randomized to twice daily treatment with fluticasone 88 μg or placebo via metered-dose inhaler and Aerochamber® for 2 years. The double blind treatment period was followed by a 1-year observational period. Lung function was measured by spirometry and oscillometry technique at 4-month intervals throughout the study. Bronchodilator reversibility and exhaled nitric oxide (ENO) studies were performed at the end of the treatment and observation periods. The primary outcome measure was the number of asthma-free days. Other secondary outcomes included number of exacerbations, use of asthma medications and lung function. These measures were chosen to reflect the progression of the disease from intermittent wheezing to persistent asthma and measurement of the extent of airflow limitation and airway reactivity.

This paper discusses some of the processes for establishing a large cluster-randomized trial of a community and primary care intervention in 16 local government areas in Victoria, Australia. The development of the trial in terms of design factors such as sample size estimates and the selection and randomization of communities to intervention or comparison is described. The intervention program to be implemented in Program of Resources, Information and Support for Mothers (PRISM) was conceived as a whole community approach to improving support for all mothers in the first 12 months after birth. A cluster-randomized trial was thus the design of choice from the outset. With a limited number of communities available, a matched-pair design with eight pairs was chosen. Sample size estimates, adjusting for the cluster randomization and the pair-matched design, showed that with eight pairs, on average, 800 women from each community would need to respond to provide sufficient power to determine a 3% reduction in the prevalence of maternal depression 6 months after birth—a reduction deemed to be a worthwhile impact of the intervention to be reliably detected at 80% power. The process of selecting suitable communities and matching them into pairs required careful collection of data on numbers of births, size of the local government areas (LGAs), and an assessment of the capacity of communities to implement the intervention. Ways of dealing with boundary issues associated with potential contamination are discussed. Methods for the selection of feasible configurations of sets of pairs and the ultimate allocation to intervention or comparison are provided in detail. Ultimately, all such studies are a balancing act between selecting the minimum number of communities to detect a meaningful outcome effect of an intervention and the maximum size budget and other resources allow.

That the test of H₀: p=p₀ versus H₁: p>p₀ can be based on a binomially distributed random variable is widely known among users of statistical methods. What is not generally known is that under certain very general conditions, it is possible to find an exact k-stage group sequential test whose total sample size is bounded above by the sample size for the single stage binomial test. That is, it is possible to find k-stage tests for detecting H₁ for which the sum of the sample sizes at each of the stages is bounded above by the sample size for the standard binomial test. This result is somewhat remarkable since the total sample size under the group sequential test setting can be strictly less than the sample size for the uniformly most powerful (UMP) one-stage binomial test. In other words, exact group sequential tests cannot only save the average sample size but can also save the maximum sample size when they are compared to the standard binomial test. In this paper, implications of existing theory are explored and a web application written by the authors is presented. No new theory is established. Applications are described and methods are demonstrated that use the web application to rapidly create efficient designs for Phase II and Pilot studies that put a minimum number of patients at risk and that facilitate the rapid progression through a scientific research agenda. While couched here in the context of clinical trials, the results may be used in any field of inquiry where inferences are made based on the size of a binomial random variable.

Prostate cancer patients receiving androgen ablation therapy experience significant physical and psychological sequelae associated with their disease and treatment. Because physical activity improves physical and psychological well-being, a lifestyle physical activity intervention may help slow or reverse the associated decline in quality of life (QOL). No studies have evaluated an intervention to improve multiple QOL domains in patients receiving androgen ablation therapy. Active for Life After Cancer is a three-group randomized controlled trial designed to evaluate the effectiveness of a lifestyle physical activity intervention (Lifestyle Program) in improving QOL. The Lifestyle Program, a 6-month behavioral skills training group, is compared to an Educational Support Program and Standard Care. The purpose of this paper is to describe the design of the randomized trial and present baseline data that will characterize the QOL of the sample. Challenges to recruitment for the trial also will be presented and discussed.

The discontinuation design has been proposed as an alternative to the classic randomized design for evaluating the effect of an experimental agent on time-to-disease progression and survival duration. With this design, all enrolled patients are treated with an experimental agent for a fixed course of therapy. Those patients with progressive disease at or before the end of this fixed period are removed from trial while those with stable disease or better are randomized to continued treatment with the experimental agent or standard of care. Simulations presented in this paper demonstrate that for realistic situations, the loss in information on patients enrolled but not randomized in the discontinuation design is of sufficient magnitude that it is underpowered as compared to the classic design of randomizing all enrolled subjects.

Postoperative ectopic bone formation affects about 40% of people undergoing elective hip replacement surgery. Despite clear evidence that a short course of perioperative nonsteroidal anti-inflammatory drugs (NSAIDs) can substantially reduce the occurrence of ectopic bone, the use of NSAID-based prophylactic therapy is uncommon in Australia or New Zealand. In part, this reflects surgeons' uncertainty about the importance of ectopic bone as a cause of impaired long-term outcome, and in part, concerns about possible increased risk for gastrointestinal complications and excess wound bleeding in patients undergoing orthopedic surgery. To address this uncertainty, a multicenter randomized controlled clinical trial is being conducted amongst 1000 patients undergoing elective total hip replacement (or revision) surgery. Patients are randomly allocated to 14 days of treatment with either 1200 mg ibuprofen (a commonly used NSAID) or matching placebo commencing within 24 h of surgery. Treatment outcomes will be assessed 6–12 months later. The primary outcome will be self-reported pain and physical function. Secondary outcomes include quality of life and physical performance measures. Patient recruitment has commenced in more than 20 orthopedic centers throughout Australia and New Zealand and will be complete by the end of October 2003. The prevention of chronic ectopic bone-related pain and disability after hip replacement surgery with anti-inflammatory drugs study (HIPAID) has been designed to provide precise and reliable information about the overall balance of risks and benefits associated with a short 14-day perioperative course of ibuprofen among individuals undergoing elective total hip replacement surgery.