AIDE: Adaptive intrapatient dose escalation designs to accelerate Phase I clinical trials.

Designing Phase I clinical trials is challenging when accrual is slow or sample size is limited. The corresponding key question is: how to efficiently and reliably identify the maximum tolerated dose (MTD) using a sample size as small as possible? We propose model-assisted and model-based designs with adaptive intrapatient dose escalation (AIDE) to address this challenge. AIDE is adaptive in that the decision of conducting intrapatient dose escalation depends on both the patient's individual safety data, as well as other enrolled patient's safety data. When both data indicate reasonable safety, a patient may perform intrapatient dose escalation, generating toxicity data at more than one dose. This strategy not only provides patients the opportunity to receive higher potentially more effective doses, but also enables efficient statistical learning of the dose-toxicity profile of the treatment, which dramatically reduces the required sample size. Simulation studies show that the proposed designs are safe, robust, and efficient to identify the MTD with a sample size that is substantially smaller than conventional interpatient dose escalation designs. Practical considerations are provided and R code for implementing AIDE is available upon request.

Tibiofemoral knee osteoarthritis progresses symmetrically by knee compartment in the GOGO cohort.

Objective: To evaluate the degree of symmetry of knee osteoarthritis (OA) structural severity and progression of participants with a mean follow-up time of 3.8 years. Design: Participants from the Genetics of Generalized Osteoarthritis (GOGO) study (n = 705) were selected on the basis of radiographic evidence of OA in at least 1 knee, availability of radiographs at baseline and follow-up, and no history of prior knee injury or surgery. Incidence and progression of osteoarthritis were determined by radiographic Kellgren-Lawrence (KL) grade; compartmental OA progression was determined by change in joint space width of lateral and medial tibiofemoral compartments. Total OA progression was the sum of change in KL grade of both knees. Results: Compared with left knees, right knees had more severe KL grades at baseline (p = 0.0002) and follow-up (p = 0.0004), McNemar's χ2 = 34.16 and 26.08, respectively; however, both knees progressed similarly (p = 0.121, McNemar's χ2 = 10.09). Compartmental changes were symmetric across knees: medial r = 0.287, p = 0.0002; lateral r = 0.593, p = 0.0002. Change in joint space width in the medial compartment was negatively correlated with change in the lateral compartment of the same knee (left knees: r = -0.293, p = 0.021; right knees: r = -0.195, p = 0.0002). Conclusions: Although right knees tended to have more severe OA at both baseline and follow-up, radiographic progression did not differ by knee and compartmental progression correlated across knees. Given this trend in generalized OA, the risk of progression for both knees should be considered, even if only one knee has radiographic OA at baseline.

Analyzing longitudinal binary data in clinical studies.

In clinical studies, it is common to have binary outcomes collected over time as repeated measures. This manuscript reviews and evaluates two popular classes of statistical methods for analyzing binary response data with repeated measures: likelihood-based Generalized Linear Mixed Model (GLMM), and semiparametric Generalized Estimating Equation (GEE). Recommendations for choice of analysis model and points to consider for implementation in clinical studies in the presence of missing data are provided based on a comprehensive literature review, as well as, a simulation study evaluating the performance of both GLMM and GEE under scenarios representative of typical clinical trial settings. Under Missing at Random (MAR) assumption, GLMM is preferred over GEE, and the SAS PROC GLIMMIX marginal model is recommended for implementing GLMM in analyzing clinical trial data. When there is an underlying continuous variable used to define the binary response, and the missing proportion is high and/or unbalanced between treatment groups, a two-step approach combining Multiple Imputation (MI) and GEE (MI-GEE) is recommended.

Study design and rationale for the Stabilization of pLaques usIng Darapladib-Thrombolysis in Myocardial Infarction (SOLID-TIMI 52) trial in patients after an acute coronary syndrome.

BACKGROUND: Higher levels of lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) are associated with a higher risk of cardiovascular events and may play a causal role in atherogenesis. Darapladib inhibits Lp-PLA(2) activity in plasma and in arterial plaques and may confer clinical benefit in preventing cardiovascular events. STUDY DESIGN: The SOLID-TIMI 52 trial is a randomized, double-blind, placebo-controlled, multicenter, event-driven trial. Approximately 13,000 subjects are being randomized to darapladib (160 mg enteric-coated tablet daily) or matching placebo within 30 days of hospitalization with an acute coronary syndrome. The primary end point is the composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Secondary end points include major and total coronary events, individual components of the primary end point, and all-cause mortality. The study will continue until approximately 1,500 primary end point events have occurred to achieve 90% power to detect a 15.5% reduction in the primary end point. The median treatment duration is anticipated to be approximately 3 years, with a total study duration of approximately 4.1 years. CONCLUSIONS: The SOLID-TIMI 52 trial will determine the clinical benefit of direct inhibition of Lp-PLA(2) activity with darapladib in patients after an acute coronary syndrome.

Efficacy of an herbal dietary supplement (Smooth Move) in the management of constipation in nursing home residents: A randomized, double-blind, placebo-controlled study.

OBJECTIVE: To investigate the efficacy and cost effectiveness of an herbal tea, Smooth Move, in nursing home residents with chronic constipation. DESIGN: Double-blind, placebo-controlled, 2-armed, parallel-group clinical trial. SETTING: A 483-bed nursing home in Allentown, Pennsylvania, operated by Lehigh County Government. PARTICIPANTS: A total of 86 nursing home residents with chronic constipation. INTERVENTIONS: Participants (n = 86) were randomly assigned to receive Smooth Move (n = 42) or a placebo (n = 44), once daily, in addition to standard treatment for chronic constipation. The study period was 28 days. MEASUREMENTS: The primary efficacy parameter was the difference in total number of bowel movements. Secondary parameters included the difference in average number of standard treatment doses dispensed, and the difference in total medication costs. RESULTS: Compared to placebo, in the intention to treat (ITT analysis) there was a statistically significant increase in the number of bowel movements in the Smooth Move group. The Smooth Move group (n = 42) compared with the placebo group (n = 44) experienced an average of 4.14 more bowel movements during the 28-day study period versus the 28-day pre-study period (P = .017). CONCLUSION: Smooth Move herbal tea, when added to the standard treatment regimen for nursing home residents with chronic constipation, increased the average number of bowel movements compared to the addition of a placebo tea.