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Clinical study protocols are the foundation of good clinical studies. Prospective and multidisciplinary collaboration that pays attention to the design of all components of the study protocol can ensure that a clinical study will answer the research questions posed in a reliable manner that is meaningful for decision-makers and patients. The ICH E9(R1) addendum on estimands and sensitivity analysis in clinical trials provides a framework for clinical study planning to ensure alignment between study objectives, design, conduct, and analysis. The estimand or clinical question posed can be regarded as the backbone of the study and the clinical study protocol should reflect estimands accordingly. In practice, stakeholders are still learning how to embrace the estimand framework and how it impacts studies and study documents. In this paper, we anticipate that a protocol structure centred around estimands, or objectives rather than endpoints alone will prevail for all types of studies. To assist sponsors during this paradigm shift, this paper provides discussion and guidance for implementing the estimand framework in protocol templates., (© 2022. The Author(s).)

Background: Prevention of IgE-binding to cellular IgE-receptors by anti-IgE (Omalizumab) is clinically effective in allergic asthma, but limited by IgE threshold-levels. To overcome this limitation, we developed a single-use IgE immunoadsorber column (IgEnio). IgEnio is based on a recombinant, IgE-specific antibody fragment and can be used for the specific extracorporeal desorption of IgE., Objective: To study safety and efficacy of IgEnio regarding the selective depletion of IgE in a randomized, open-label, controlled pilot trial in patients with allergic asthma and to investigate if IgEnio can bind IgE-Omalizumab immune complexes., Methods: Fifteen subjects were enrolled and randomly assigned to the treatment group (n=10) or to the control group (n=5). Immunoadsorption was done by veno-venous approach, processing the twofold calculated plasma volume during each treatment. A minimum average IgE-depletion of 50% after the last cycle in the intention-to-treat population was defined as primary endpoint. Safety of the treatment was studied as secondary endpoint. In addition, possible changes in allergen-specific sensitivity were investigated, as well as clinical effects by peak flow measurement and symptom-recording. The depletion of IgE-Omalizumab immune complexes was studied in vitro. The study was registered at clinicaltrials.gov (NCT02096237) and conducted from December 2013 to July 2014., Results: IgE immunoadsorption with IgEnio selectively depleted 86.2% (±5.1% SD) of IgE until the end of the last cycle (p<0.0001). Removal of pollen allergen-specific IgE was associated with a reduction of allergen-specific basophil-sensitivity and prevented increases of allergen-specific skin-sensitivity and clinical symptoms during pollen seasons. IgEnio also depleted IgE-Omalizumab immune complexes in vitro. The therapy under investigation was safe and well-tolerated. During a total of 81 aphereses, 2 severe adverse events (SAE) were recorded, one of which, an episode of acute dyspnea, possibly was related to the treatment and resolved after administration of antihistamines and corticosteroids., Conclusions: This pilot study indicates that IgE immunoadsorption with IgEnio may be used to treat patients with pollen-induced allergic asthma. Furthermore, the treatment could render allergic patients with highly elevated IgE-levels eligible for the administration of Omalizumab and facilitate the desorption of IgE-Omalizumab complexes. This study was funded by Fresenius Medical Care Deutschland GmbH, Bad Homburg, Germany., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Volume status, lean and fat tissue are gaining interest as prognostic predictors in patients on dialysis. Comparative data in peritoneal dialysis (PD) versus haemodialysis (HD) patients are lacking., Methods: In a cohort of PD (EuroBCM) and HD (Euclid database) patients, matched for country, gender, age and dialysis vintage, body composition was assessed by bioimpedance spectroscopy (BCM, Fresenius Medical Care). Time-averaged volume overload (TAVO) was defined as the mean of pre- and post-dialysis volume overload (VO), and relative (%) (TA)VO as (TA)VO/ECV., Results: Four hundred and ninety-one matched pairs (55.2% males, median age 60.0 years) were included. The body mass index (BMI, PD = 26.5 ± 4.7 versus HD = 25.9 ± 4.6 kg/m(2), P = 0.18 in males and 27.4 ± 5.8 versus 27.5 ± 6.6 kg/m(2), P = 0.75 in females) and fat tissue index (males: 11.5 ± 5.3 versus 11.4 ± 5.4 kg/m(2), P = 0.90, females: 14.8 ± 6.7 versus 15.4 ± 7.2 kg/m(2), P = 0.30) were not different in PD versus HD patients, whereas the lean tissue index (LTI) was higher in PD versus HD patients (males: 14.5 ± 3.4 versus 13.7 ± 3.1 kg/m(2), P = 0.001, females: 12.6 ± 3.3 versus 11.5 ± 2.6 kg/m(2), P < 0.0001). VO/extracellular water (ECW) was not different between PD versus just before the HD treatment (males: 10.8 ± 12.1 versus 9.2 ± 10.2%, P = 0.09; females: 6.5 ± 10.8 versus 7.7 ± 9.4%, P = 0.19). The relative TAVO was higher in PD versus HD (10.8 ± 12.1% versus 3.2 ± 11.2%, and 6.5 ± 10.8% versus 1.2 ± 10.9%, both P < 0.0001)., Conclusions: The LTI was impaired, and this was more in males versus females, but was better preserved on PD versus HD, whereas fat tissue index (FTI) was increased, but not different between PD and HD. Volume overload was more present in PD versus HD when TAVO, but not when predialysis volume status, was used as a reference.

Background: Euvolemia is an important adequacy parameter in peritoneal dialysis (PD) patients. However, accurate tools to evaluate volume status in clinical practice and data on volume status in PD patients as compared to healthy population, and the associated factors, have not been available so far., Methods: We used a bio-impedance spectroscopy device, the Body Composition Monitor (BCM) to assess volume status in a cross-sectional cohort of prevalent PD patients in different European countries. The results were compared to an age and gender matched healthy population., Results: Only 40% out of 639 patients from 28 centres in 6 countries were normovolemic. Severe fluid overload was present in 25.2%. There was a wide scatter in the relation between blood pressure and volume status. In a multivariate analysis in the subgroup of patients from countries with unrestricted availability of all PD modalities and fluid types, older age, male gender, lower serum albumin, lower BMI, diabetes, higher systolic blood pressure, and use of at least one exchange per day with the highest hypertonic glucose were associated with higher relative tissue hydration. Neither urinary output nor ultrafiltration, PD fluid type or PD modality were retained in the model (total R² of the model = 0.57)., Conclusions: The EuroBCM study demonstrates some interesting issues regarding volume status in PD. As in HD patients, hypervolemia is a frequent condition in PD patients and blood pressure can be a misleading clinical tool to evaluate volume status. To monitor fluid balance, not only fluid output but also dietary input should be considered. Close monitoring of volume status, a correct dialysis prescription adapted to the needs of the patient and dietary measures seem to be warranted to avoid hypervolemia.

Insertion of the human non-LTR retrotransposon LINE-1 (L1) into chromosomal DNA is thought to be initiated by a mechanism called target-primed reverse transcription (TPRT). This mechanism readily accounts for the attachment of the 3'-end of an L1 copy to the genomic target, but the subsequent integration steps leading to the attachment of the 5'-end to the chromosomal DNA are still cause for speculation. By applying bioinformatics to analyze the 5' junctions of recent L1 insertions in the human genome, we provide evidence that L1 uses at least two distinct mechanisms to link the 5'-end of the nascent L1 copy to its genomic target. While 5'-truncated L1 elements show a statistically significant preference for short patches of overlapping nucleotides between their target site and the point of truncation, full-length insertions display no distinct bias for such microhomologies at their 5'-ends. In a second genome-wide approach, we analyzed Alu elements to examine whether these nonautonomous retrotransposons, which are thought to be mobilized through L1 proteins, show similar characteristics. We found that Alu elements appear to be predominantly integrated via a pathway not involving overlapping nucleotides. The results indicate that a cellular nonhomologous DNA end-joining pathway may resolve intermediates from incomplete L1 retrotransposition events and thus lead to 5' truncations.

Background and Purpose: The volume of decreased cerebral blood flow (CBF) in acute stroke perfusion-weighted imaging frequently overestimates final infarct volume. We hypothesized that surviving tissue exists even in patients without recanalization and tried to determine perfusion thresholds from initial MR imaging., Methods: Stroke MR imaging including MR angiography was carried out at days 0, 1, and 7 after stroke onset in 19 patients without recanalization at least until day 1. The following lesions were defined: L0 = diffusion restriction at day 0; LG1 = lesion growth until day 1; LG7 = lesion growth until day 7; ST7 = initially hypoperfused, but surviving tissue. These lesions were transferred on initial MR imaging within 4.7 hours and perfusion values at day 0 were determined., Results: Median lesion volume L0 at day 0 was 18.2 mL and increased to 39.4 and 43.8 mL at days 1 and 7. Volume of decreased rCBF not progressing to infarction was 148.5 mL (ST7). Mean ST7 perfusion values were different from L0 and LG1, but only mean relative cerebral blood volume (rCBV) was different from LG7, discriminating survival against death of tissue. A threshold value of 0.82 CBV for death versus survival was determined with a sensitivity of 0.56 and specificity of 0.95. Carotid T occlusions showed the greatest potential of lesion growth., Conclusion: Even when vessel occlusion persists, hypoperfused tissue on MR imaging does not necessarily progress toward infarction. The most conclusive inferences can be drawn from CBV images. The site of arterial occlusion also determines progression to infarction.

Background and Purpose: We tested the hypothesis that early diffusion- and perfusion-weighted MRI (DWI and PWI, respectively) allows the prediction of malignant middle cerebral artery (MCA) infarction (MMI)., Methods: Thirty-seven patients with acute MCA infarction and proximal vessel occlusion (carotid-T, MCA main stem) were studied by DWI, PWI, and MR angiography within 6 hours of symptom onset. Eleven patients developed MMI, defined by decline of consciousness and radiological signs of space-occupying brain edema. Lesion volumes were retrospectively defined as apparent diffusion coefficient <80% (ADC<80%) and time to peak >+4 seconds (TTP>+4s) compared with the unaffected hemisphere. ADC decrease within the infarct core (ADCcore) and relative ADC within the ADC<80% lesion (rADClesion) were measured. Neurological deficit at admission was assessed with the National Institutes of Health Stroke Scale (NIHSS)., Results: Patients with MMI showed larger ADC<80% (median, 157 versus 22 mL; P<0.001) and TTP>+4s (208 versus 125 mL; P<0.001) lesion volumes, smaller TTP/ADC mismatch ratio (1.5 versus 5.5; P<0.001), lower ADCcore values (290 versus 411 mm2/s; P<0.001), lower rADClesion (0.60 versus 0.66; P=0.001), higher frequency of carotid-T occlusion (64% versus 15%; P=0.006), and higher NIHSS score at admission (20 versus 15; P=0.001). Predictors of MMI were as follows for sensitivity and specificity, respectively: ADC<80% >82 mL, 87%, 91%; TTP>+4s >162 mL, 83%, 75%; TTP/ADC mismatch ratio <2.4, 80%, 79%; ADCcore <300 mm2/s, 83%, 85%; rADClesion <0.62, 79%, 74%; and NIHSS score at admission > or =19, 96%, 72%., Conclusions: Quantitative analysis of early DWI and PWI parameters allows the prediction of MMI and can help in the selection of patients for aggressive tissue-protective therapy.

Background and Purpose: Previous acute stroke studies found diffusion-weighted (DW) imaging superior to CT for detection of early ischemic signs (EIS). However, these findings were confounded by a large time interval in favor of DW imaging. We compared DW images and CT scans obtained with a short time delay in patients with acute stroke to define the sensitivity and interrater agreement of both imaging techniques., Methods: CT scans and DW images were obtained within 6 hours of symptom onset in 46 patients with acute stroke. Three neuroradiologists and three neurologists reviewed the images for EIS in five regions of the middle cerebral artery (MCA) territory and estimated the extent of EIS (< or > one-third of the MCA territory)., Results: The mean delay between imaging with both modalities was 24.5 minutes (range, 10-41 minutes). Forty-five of 46 patients had an ischemic stroke. EIS were seen on 33 of 45 CT scans (73% sensitivity; 95% confidence interval [CI]: 58-85%) and on 42 of 45 DW images (93% sensitivity; 94% CI: 82-99%). Interrater agreement was moderate (kappa = 0.57) for CT and excellent (kappa = 0.85) for DW imaging. CT studies had a moderate interrater agreement for estimation of EIS greater than one-third of the MCA territory (kappa = 0.40), whereas DW imaging showed good results (kappa = 0.68). Sensitivity for detection of greater than one-third of the MCA territory was equally poor (57%, 95% CI: 29-82%) for both CT and DW imaging., Conclusion: DW imaging helped identify EIS with higher sensitivity than that of CT. The interrater variability of the one-third rule was high for CT, and thus the clinical applicability of CT is limited. Our results support the application of stroke MR imaging for the treatment of patients with acute stroke.

Background and Purpose: The goals of this study were to examine MRI baseline characteristics of patients with acute ischemic stroke (AIS) and to study the influence of intravenous tissue plasminogen activator (tPA) on MR parameters and functional outcome using a multicenter approach., Methods: In this open-label, nonrandomized study of AIS patients with suspected anterior circulation stroke, subjects received a multiparametric stroke MRI protocol (diffusion- and perfusion-weighted imaging and MR angiography) within 6 hours after symptom onset and on follow-up. Patients were treated either with tPA (thrombolysis group) or conservatively (no thrombolysis group). Functional outcome was assessed on day 90 (modified Rankin Score; mRS)., Results: We enrolled 139 AIS patients (no thrombolysis group, n=63; thrombolysis group, n=76). Patients treated with tPA were more severely affected (National Institutes of Health Stroke Scale score, 10 versus 13; P=0.002). Recanalization rates were higher in the thrombolysis group (Thrombolysis in Myocardial Infarction criteria 1 through 3 on day 1; 66.2% versus 32.7%; P<0.001). Proximal vessel occlusions resulted in larger infarct volumes and worse outcome (P=0.02). Thrombolysis was associated with a better outcome regardless of the time point of tPA treatment (< or =3 hours or 3 to 6 hours) (univariate analysis: mRS < or =2, P=0.017; mRS < or =1, P=0.023). Age (P=0.003), thrombolytic therapy at 0 to 6 hours (P=0.01), recanalization (P=0.016), lesion volume on day 7 (P=0.001), and initial National Institutes of Health Stroke Scale score (P=0.001) affected functional outcome (mRS on day 90) positively (multivariate analysis). The time point of tPA therapy affected the recanalization rate (P=0.024) but not final infarct volume., Conclusions: In this pilot study, tPA therapy had a beneficial effect on vessel recanalization and functional outcome. Multiparametric MRI delineates tissue at risk of infarction in AIS patients, which may be helpful for the selection of patients for tPA therapy. tPA therapy appeared safe and effective beyond a 3-hour time window. This study delivers the rationale for a randomized, MR-based tPA trial.