Sequential, Multiple Assignment, Randomized Trials
Susan Halabi, Stefan Michiels in Textbook of Clinical Trials in Oncology, 2019
A crossover study is a repeated measures design. In the simplest scenario, patients are exposed to two treatments in succession, allowing for an adequate washout period between treatment administrations to reduce any carryover effects. Carryover effects are those observable or unobservable effects of the first agent that remain in the body after the first treatment is administered and that, if unaccounted for, could confound the outcomes observed following administration of the second agent. A pre-specified period of time between the first and second treatment administrations, known as a “washout” period, is generally used to mitigate any carryover effects. The endpoint of interest for crossover studies is evaluated for all patients after each treatment course. In the crossover design, patients are used as their own control. Although crossover designs are infrequently used in oncology clinical trials due to the fact that traditional endpoints are often non-reversible events (e.g., response, time to progression, survival, etc.), there remains some overlap between SMART and crossover design. SMARTs, as described above, include sequential randomizations based on an intermediate outcome whereas, in a designed crossover, each patient is first treated with one agent followed by the other. In crossover designs, however, all participants crossover, so that crossover is not dependent on an intermediate outcome.
Generics and Biosimilars
Shein-Chung Chow in Innovative Statistics in Regulatory Science, 2019
As indicated earlier, a crossover design is often employed for bioequivalence assessment. In a crossover study, each drug product is administered to each subject. Thus, estimated (approximate) within-subject variance can be made to serve to address switchability and interchangeability. For a parallel-group study, each drug product is administered to a different group of subjects. Thus, we can only estimate total variance (between and within subject variances) not individual variance components. For follow-on biologics with long half-lives, crossover study would be ineffective and unethical. In this case, we need to undertake study with parallel groups. However, a parallel-group study does not provide an estimate for within-subject variation (since there is no R vs. R).
Confidence Intervals
Marcello Pagano, Kimberlee Gauvreau in Principles of Biostatistics, 2018
As a second example, methylphenidate is a drug that is widely used in the treatment of attention-deficit disorder. As part of a crossover study, ten children between the ages of 7 and 12 who suffered from this disorder were assigned to receive the drug and ten were given a placebo [7]. After a fixed period of time, treatment was withdrawn from all 20 children. Subsequently, the children who had received methylphenidate were given the placebo, and those who had received the placebo now got the drug. (This is what is meant by a crossover study.) Measures of each child’s attention and behavioral status, both on the drug and on the placebo, were obtained using an instrument called the Parent Rating Scale. Distributions of these scores are approximately normal with unknown means and standard deviations. In general lower scores indicate an increase in attention. We wish to estimate the mean attention rating scores for children taking methylphenidate and for those taking the placebo.
An empirical, pragmatic approach applying reflection in interaction approach to manual therapy treatments
Published in Physiotherapy Theory and Practice, 2021
Another difficulty in considering the specificity of treatment effects is more subtle and relates to study design. Typical randomized controlled trials (RCTs) compare groups and are, by their nature, incapable of detecting the presence of individual (as distinct from group) responses. A more complete discussion of the difficulties in applying RCTs to clinical practice (Kerry, 2017) and the types of study designs that are necessary for investigating individual responses (Hecksteden et al, 2015; Senn, 2001) can be found elsewhere. Briefly, determining if individuals respond consistently in ways that may be different from group responses requires crossover study designs where individuals receive repeated applications of more than one intervention. The heterogeneity and instability over time of musculoskeletal conditions combined with the heterogeneity of treatments (Snodgrass, Rivett, and Robertson, 2006) and greater variability between than within operators (Seffinger et al, 2004) make the application of such study designs to musculoskeletal conditions particularly difficult. To date, we know of no studies that specifically consider the extent of specificity of individual responses to manual therapy treatments.
Brain activity and connectivity changes in response to glucose ingestion
Published in Nutritional Neuroscience, 2020
A. M. van Opstal, A. Hafkemeijer, A. A. van den Berg-Huysmans, M. Hoeksma, C. Blonk, H. Pijl, S. A. R. B. Rombouts, J. van der Grond
A limitation of our study is that it was performed only in a very homogenous group of male volunteers and it can be expected that sex differences are present, since it is known that there are several sex-specific differences in responses to satiation34 and energy metabolism,35 which decreases the generalizability of our findings. A further limitation is that because our participants were fasted during the experiment extrapolation of our results to a non-fasted state might be limited, especially because we did not take into account the normal eating behavior of the participants when not asked to remain fasted. Furthermore, as the brain consumes large amounts of glucose by default, oral consumption of a glucose dose may have general and nonspecific effects on brain activity that are not specifically related to hedonic or energy regulating aspects of glucose intake. Additionally, because we used only a glucose stimulus, to be able to generalize our results to everyday sugar consumption future studies would have to be done using other (more complex) sugars and sweeteners that are commonly used in food and beverages. A strength of our study was our crossover study design, which allowed for a reliable within-subject comparison between interventions as participants were their own controls. A further strength was the hypothesis-free approach taking into account the whole brain changes versus a region of interest approach that makes assumptions beforehand.
Bisoprolol transdermal patch improves orthostatic hypotension in patients with chronic heart failure and hypertension
Published in Clinical and Experimental Hypertension, 2020
Shunsuke Kiuchi, Shinji Hisatake, Takayuki Kabuki, Takashi Oka, Shintaro Dobashi, Takahiro Fujii, Takahide Sano, Takanori Ikeda
The most notable limitation of the present study is that this is a single-arm study and not a crossover design. Also, 12 of 57 subjects dropped out of the study. The subjects with skin diseases were excluded; however, the biggest cause of dropout was attributed to skin problems. Skin problems were caused, for the most part, in the summer. If a crossover design was performed in the present study, the follow-up duration required will be 1 year; thus, we could not perform a crossover study. Another major study limitation is not measuring blood concentrations. We standardized the time regarding taking the bisoprolol fumarate tablet or applying the bisoprolol transdermal patch in the examinations because we could not measure blood concentrations. And, it is possible that patients of each groups were not enough when we divided into OH and non-OH patients. In order to avoid these biases, a prospective crossover study with a larger number of subjects is necessary.
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