A Likelihood-Based Approach for Computing the Operating Characteristics of the Standard Phase I Clinical Trial Design

In phase I clinical trials, the standard ‘3+3’ design has passed the test of time and survived various sample size adjustments, or other dose-escalation dynamics. The objective of this study is to provide a probabilistic support for analyzing the heuristic performance of the ‘3+3’ design. Our likelihood method is based on the evidential paradigm that uses the likelihood ratio to measure the strength of statistical evidence for one simple hypothesis over the other. We compute the operating characteristics and compare the behavior of the standard algorithm under different hypotheses, levels of evidence, and true (or best guessed) toxicity rates. Given observed toxicities per dose level, the likelihood-ratio is evaluated according to a certain k threshold (level of evidence). Under an assumed true toxicity scenario the following statistical characteristics are computed and compared: i) probability of weak evidence, ii) probability of favoring H1 under H1(analogous to 1-α), iii) probability of favoring H2 under H2 (analogous to 1-β). This likelihood method allows consistent inferences to be made and evidence to be quantified regardless of cohort size. Moreover, this approach can be extended and used in phase I designs for identifying the highest acceptably safe dose and is akin to the sequential probability ratio test

S1P, dihydro-S1P and C24:1-ceramide levels in the HDL-containing fraction of serum inversely correlate with occurrence of ischemic heart disease

BACKGROUND: The lysosphingolipid sphingosine 1-phosphate (S1P) is carried in the blood in association with lipoproteins, predominantly high density lipoproteins (HDL). Emerging evidence suggests that many of the effects of HDL on cardiovascular function may be attributable to its S1P cargo. METHODS: Here we have evaluated how levels of S1P and related sphingolipids in an HDL-containing fraction of human serum correlate with occurrence of ischemic heart disease (IHD). To accomplish this we used liquid chromatography-mass spectrometry to measure S1P levels in the HDL-containing fraction of serum (depleted of LDL and VLDL) from 204 subjects in the Copenhagen City Heart Study (CCHS). The study group consisted of individuals having high serum HDL cholesterol (HDL-C) (females:≥73.5 mg/dL; males:≥61.9 mg/dL) and verified IHD; subjects with high HDL-C and no IHD; individuals with low HDL-C (females:≤38.7 mg/dL; males:≤34.1 mg/dL) and IHD, and subjects with low HDL-C and no IHD. RESULTS: The results show a highly significant inverse relationship between the level of S1P in the HDL-containing fraction of serum and the occurrence of IHD. Furthermore, an inverse relationship with IHD was also observed for two other sphingolipids, dihydro-S1P and C24:1-ceramide, in the HDL-containing fraction of serum. Additionally, we demonstrated that the amount of S1P on HDL correlates with the magnitude of HDL-induced endothelial cell barrier signaling. CONCLUSIONS: These findings indicate that compositional differences of sphingolipids in the HDL-containing fraction of human serum are related to the occurrence of IHD, and may contribute to the putative protective role of HDL in IHD

National Institutes of Health Stroke Scale An Alternative Primary Outcome Measure for Trials of Acute Treatment for Ischemic Stroke

Background and Purpose- The modified Rankin Scale (mRS) at 3 months is the most commonly used primary outcome measure in stroke treatment trials, but it lacks specificity and requires long-term follow-up interviews, which consume time and resources. An alternative may be the National Institutes of Health Stroke Scale (NIHSS), early after stroke. Our aim was to evaluate whether the NIHSS assessed within 1 week after treatment could serve as a primary outcome measure for trials of acute treatment for ischemic stroke. Methods- We used data from 2 randomized controlled trials of endovascular treatment for ischemic stroke: the positive MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands; N=500) and the neutral IMS (Interventional Management of Stroke) III trial (N=656). We used a causal mediation model, with linear and ordinal logistic regression adjusted for confounders, to evaluate the NIHSS 24 hours and 5 to 7 days after endovascular treatment as primary outcome measures (instead of the mRS at 3 months) in both trials. Patients who had died before the NIHSS was assessed received the maximum score of 42. NIHSS+1 was then log10-transformed. Results- In both trials, there was a significant correlation between the NIHSS at 24 hours and 5 to 7 days and the mRS. In MR CLEAN, we found a significant effect of endovascular treatment on the mRS and on the NIHSS at 24 hours and 5 to 7 days. After adjustment for NIHSS at 24 hours and 5 to 7 days, the effect of endovascular treatment on the mRS decreased from common odds ratio 1.68 (95% CI, 1.22-2.32) to respectively 1.36 (95% CI, 0.97-1.91) and 1.24 (95% CI, 0.87-1.79), indicating that treatment effect on the mRS is in large part mediated by the NIHSS. In the IMS III trial there was no treatment effect on the NIHSS at 24 hours and 5 to 7 days, corresponding with the absence of a treatment effect on the mRS. Conclusions- The NIHSS within 1 week satisfies the requirements for a surrogate end point and may be used as a primary outcome measure in trials of acute treatment for ischemic stroke, particularly in phase II(b) trials. This could reduce stroke-outcome assessment to its essentials (ie, neurological deficit), and reduce trial duration and costs. Whether and under which conditions it could be used in phase III trials requires a debate in the field with all parties. Clinical Trial Registration- URL: http://www.isrctn.com. Unique identifier: ISRCTN10888758; https://www.clinicaltrials.gov. Unique identifier: NCT00359424.</p

National Institutes of Health Stroke Scale: An Alternative Primary Outcome Measure for Trials of Acute Treatment for Ischemic Stroke

Background and Purpose- The modified Rankin Scale (mRS) at 3 months is the most commonly used primary outcome measure in stroke treatment trials, but it lacks specificity and requires long-term follow-up interviews, which consume time and resources. An alternative may be the National Institutes of Health Stroke Scale (NIHSS), early after stroke. Our aim was to evaluate whether the NIHSS assessed within 1 week after treatment could serve as a primary outcome measure for trials of acute treatment for ischemic stroke. Methods- We used data from 2 randomized controlled trials of endovascular treatment for ischemic stroke: the positive MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands; N=500) and the neutral IMS (Interventional Management of Stroke) III trial (N=656). We used a causal mediation model, with linear and ordinal logistic regression adjusted for confounders, to evaluate the NIHSS 24 hours and 5 to 7 days after endovascular treatment as primary outcome measures (instead of the mRS at 3 months) in both trials. Patients who had died before the NIHSS was assessed received the maximum score of 42. NIHSS+1 was then log10-transformed. Results- In both trials, there was a significant correlation between the NIHSS at 24 hours and 5 to 7 days and the mRS. In MR CLEAN, we found a significant effect of endovascular treatment on the mRS and on the NIHSS at 24 hours and 5 to 7 days. After adjustment for NIHSS at 24 hours and 5 to 7 days, the effect of endovascular treatment on the mRS decreased from common odds ratio 1.68 (95% CI, 1.22-2.32) to respectively 1.36 (95% CI, 0.97-1.91) and 1.24 (95% CI, 0.87-1.79), indicating that treatment effect on the mRS is in large part mediated by the NIHSS. In the IMS III trial there was no treatment effect on the NIHSS at 24 hours and 5 to 7 days, corresponding with the absence of a treatment effect on the mRS. Conclusions- The NIHSS within 1 week satisfies the requirements for a surrogate end point and may be used as a primary outcome measure in trials of acute treatment for ischemic stroke, particularly in phase II(b) trials. This could reduce stroke-outcome assessment to its essentials (ie, neurological deficit), and reduce trial duration and costs. Whether and under which conditions it could be used in phase III trials requires a debate in the field with all parties. Clinical Trial Registration- URL: http://www.isrctn.com. Unique identifier: ISRCTN10888758; https://www.clinicaltrials.gov. Unique identifier: NCT00359424

Eine Einführung in die Inverted-Classroom-Methode in der medizinischen Ausbildung

Zielgruppe: Der Workshop richtet sich an alle Personen, die sich für die Inverted Classroom Methode(ICM) interessieren und diese ggf. für eigene Lehrprojekte anwenden möchten Lernziele: Ziel des Workshops ist es, die Teilnehmer zu befähigen, die ICM auf die eigene Lehre anzuwenden. Inhalt: Der Workshop gibt eine Einführung in die ICM, skizziert ihre Vor- und Nachteile unter Einbeziehung aktueller Forschungsergebnisse und vermittelt praktische Fertigkeiten, um eigene Konzept für die Lehre entwickeln zu können. Dabei werden zusätzlich Themen wie Video-und Screencasterstellung, Open Educational Resources und Urheberrechte skizziert. Ablauf: Der Workshop selbst ist nach der ICM konzipiert. Das bedeutet, dass sich die Teilnehmer bereits im Vorfeld in einer Online-Phase das notwendige Faktenwissen aneignen, um in der Präsenzphase das erlernte Wissen in Kleingruppen anzuwenden und ICM-Konzepte für die eigene Lehre zu entwickeln. Diese Konzepte werden am Ende in der Gruppe vorgestellt und diskutier

ALIAS (Albumin in Acute Ischemic Stroke) Trials

BACKGROUND AND PURPOSE: The Albumin in Acute Stroke (ALIAS) Part 1 and 2 Trials evaluated whether 25% human serum albumin improves clinical outcomes after acute ischemic stroke above and beyond standard of care using similar protocols. The Part 1 Trial ended prematurely due to safety concerns, and the Part 2 Trial terminated early due to futility of finding a statistically significant effect of ALB over saline (control) administration. We combine the subject-level data of the Part 1 and 2 Trials to re-evaluate the efficacy and safety outcomes with the larger sample size. METHODS: The combined data analyses closely follow those conducted in the Part 2 Trial. The primary outcome is the composite of the modified Rankin Scale and the NIH Stroke Scale defined as a composite of mRS 0-1 and/or NIHSS 0-1 at 90 days from randomization. The unadjusted analyses use a simple Chi-square test and those adjusting for baseline covariates use a generalized linear model with log link (to obtain relative risks). RESULTS: The participant characteristics at baseline were generally similar between the treatment groups and between Trials; however, thrombolysis use was greater in Part 2 (84% vs 75%), and the upper age limit imposed in Part 2 resulted in a younger sample (mean age in Part 1 was 69 vs 64 in Part 2). In the combined sample the proportions of good outcome in the two treatment groups were identical (41%). Similar results were observed in all secondary efficacy outcomes. Pulmonary edema was a consistent safety concern, with a six-fold increase in the ALB arm (13%) compared to Saline (2%) (RR=7.76, 95% CI 3.87-15.57). CONCLUSIONS: Treatment with intravenous albumin 25% at 2 g/kg was not associated with improved outcome at 90 days and was associated with increased rates of intracerebral hemorrhage and pulmonary edema

Determining the Joint Effect of Obesity and Diabetes on All-Cause Mortality and Cardiovascular-Related Mortality following an Ischemic Stroke

Although obesity and diabetes mellitus, or diabetes, are independently associated with mortality-related events (e.g., all-cause mortality and cardiovascular-related mortality) following an ischemic stroke, little is known about the joint effect of obesity and diabetes on mortality-related events following an ischemic stroke. The aim of this study is to evaluate the joint effect of obesity and diabetes on mortality-related events in subjects with a recent ischemic stroke. Data from the multicenter Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial was analyzed for this study. The joint effect of obesity and diabetes on mortality-related events was estimated via Cox proportional hazards regression models. No difference in the hazard of all-cause mortality following an ischemic stroke was observed between obese subjects with diabetes and underweight/normal-weight subjects without diabetes. In contrast, obese subjects with diabetes had an increased hazard of cardiovascular-related mortality following an ischemic stroke compared with underweight/normal-weight subjects without diabetes. Additionally, there was evidence of an attributable proportion due to interaction as well as evidence of a highly statistically significant interaction on the multiplicative scale for cardiovascular-related mortality. In this clinical trial cohort of ischemic stroke survivors, obesity and diabetes synergistically interacted to increase the hazard of cardiovascular-related mortality