Practical and Optimal Crossover Designs for Clinical Trials

Crossover designs have received great attention in clinical trials, as they allow subjects to serve as their own controls and gain such advantage as higher efficiency and smaller sample size over parallel designs, because the within-subject variability is in general smaller than between-subject variability. Response-adaptive crossover designs allow clinical trials to adapt and respond to the information acquired during the trials to achieve various objectives. Adaptive designs have been considered to allocate more subjects to superior treatments, improve statistical efficiency, reduce the sample size for cost savings, increase the sample size to maintain prespecified statistical power, or include auxiliary information. We focus on an adaptive allocation scheme to maximize the benefits from superior treatments, while maintaining a sufficiently high level of statistical efficiency, controlled by a suitable weight parameter. We review and discuss the strategy of incorporating multiple objectives, while advocating a regression type estimation approach via the Generalized Estimating Equations method. We show that the multiple objectives can be successfully incorporated to construct a spectrum of designs, ranging over various efficiencies and trial outcomes of success. Moreover, the adaptive allocation scheme successfully constructs designs with a desired efficiency, as illustrated by practical two- and three-period designs

Optimal N-of-1 Clinical Trials for Individualized Patient Care and Aggregated N-of-1 Designs

Precision medicine typically refers to the use of genomic signatures of patients to assign more effective therapies to treat patients, or, for improved diagnosis of the early onset of a disease so that interventions can be delivered to prevent or delay the disease progression. Because the aim is to provide individualized patient treatment, such single-person trials are called N-of-1 trials. This chapter reviews fundamental ideas, models, and construction of optimal designs for N-of-1 trials, which are invariably constructed from crossover trials, where each patient receives a random sequence of trial treatments over time. We construct examples of universally optimal N-of-1 designs for comparing two treatments under various correlation structure assumptions and discuss how N-of-1 trials may be combined to form optimal aggregated N-of-1 trials for assessing average treatment effects for two or more treatments

Transarterial chemoembolization versus resection for intermediate-stage (BCLC B) hepatocellular carcinoma

Background/Aims: Several studies have suggested that surgical resection (SR) can provide a survival benefit over transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC) at the intermediate stage according to the Barcelona Clinic Liver Cancer (BCLC) staging system. However, the criteria for SR remain to be determined. This study compared the long-term outcome of intermediate-stage HCC patients treated by either TACE or SR as a primary treatment modality, with the aim of identifying the patient subgroup that gained a survival benefit by either modality. Methods: In total, 277 BCLC intermediate-stage HCC patients treated by either TACE (N=225) or SR (N=52) were analyzed. Results: The overall median survival time was significantly better for SR than TACE (61 vs. 30 months, P=0.002). Decision-tree analysis divided patients into seven nodes based on tumor size and number, serum alpha-fetoprotein (AFP) level, and Child-Pugh score, and these were then simplified into four subgroups (B1–B4) based on similarities in the overall hazard rate. SR provided a significant survival benefit in subgroup B2, characterized by ‘oligo’ (2–4) nodules of intermediate size (5–10 cm) when the AFP levels was <400 ng/ml, or ‘oligo’ (2–4) nodules of small to intermediate size (<10 cm) plus a Child-Pugh score of 5 when the AFP level was ≥400 ng/mL (median survival 73 vs. 28 months for SR vs. TACE respectively; P=0.014). The survival rate did not differ significantly between SR and TACE in the other subgroups (B1 and B3). Conclusion: SR provided a survival benefit over TACE in intermediate-stage HCC, especially for patients meeting certain criteria. Re-establishing the criteria for optimal treatment modalities in this stage of HCC is needed to improve survival rates

Morphine Does Not Affect Myocardial Salvage in ST-Segment Elevation Myocardial Infarction

<div><p>Recent studies have proposed intravenous (IV) morphine is associated with delayed action of antiplatelet agents in acute myocardial infarction. However, it is unknown whether morphine results in increased myocardial damage in ST-segment elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PCI). We investigated myocardial salvage index (MSI) to determine whether IV morphine affects myocardial injury adversely in STEMI patients undergoing primary PCI. 299 STEMI patients underwent contrast-enhanced magnetic resonance imaging a median of 3 days after PCI. Infarct size was measured on delayed-enhancement imaging, and area at risk was quantified on T2-weighted imaging. MSI was calculated as ‘[area at risk–infarct size] X 100 / area at risk’. IV morphine was administrated in 32.1% of patients. Patients treated with morphine had shorter symptom to balloon time and higher prevalence of Thrombolysis in Myocardial Infarction flow grade 0 or 1. The morphine group showed a trend toward larger MSI and infarct size and significantly greater area at risk than the non-morphine group. After propensity score matching (90 pairs), MSI was similar between the morphine and non-morphine group (46.1% versus 43.5%, <i>P</i> = .11), and infarct size and area at risk showed no difference. In propensity score-matched analysis, IV morphine prior to primary PCI in STEMI patients did not cause adverse impacts on myocardial salvage.</p></div

Myocardial salvage index in the total population and propensity score-matched population.

<p>Myocardial salvage index was greater in patients treated with morphine in crude analysis, but there was no significant difference between the two groups after propensity score-matched analysis.</p

Predictors of high myocardial salvage index (>44%).

<p>Predictors of high myocardial salvage index (>44%).</p

Example CMR images of reperfused inferior STEMI.

<p>Short-axis slices of T2-weighted image (A) and the corresponding delayed hyperenhancement image (B) in patients with inferior ST-segment elevation myocardial infarction. The extent of area at risk (C) and infarct size (D) are indicated as by yellow lines.</p

Cardiac magnetic resonance findings.

<p>Cardiac magnetic resonance findings.</p

Study population.

<p>Study population.</p