ObsEva (Switzerland)

Adaptive trial designs have the potential to address common challenges in drug development; they decrease timelines and costs of early drug development and efficiently create data that support future trials in target populations. While allowing for flexibility and evolution, adaptive strategies introduce some complexity to the design and implementation of trial protocols. Previously published work by the authors include a retrospective analysis of time savings using adaptive design and a systematic, 3- step methodology for writing early-phase adaptive integrated protocols. This article builds on the authors' published work demonstrating the practical implementation of the adaptive protocol writing methodology and discussing the challenges and efficiencies. It describes the integration of an early development program of OBE022, a novel, oral, selective prostaglandin F2a receptor antagonist, intended as a treatment for preterm labor, using 2 interdependent, adaptive trial protocols. The program consisted of first-in-human single and multiple ascending dose parts with assessments of food effect, cardiac safety, proof of concept, and interactions of OBE022 with 4 standard of care medicines. The manuscript shows how the trials were tailored to OBE022's pharmacokinetic and pharmacodynamic characteristics and its therapeutic indication. The use of 2 large interdependent, adaptive protocols was facilitated by the United Kingdom's (UK's) regulatory environment and its acceptance of a rules-guided progression through the program. Changes to the planned trial conduct could be made without impacting on timelines, because they used predefined adaptive options within their authorized boundaries, and could therefore be made as nonsubstantial amendments. The program was successful and achieved its objectives. It was efficient and fast: it required a small number of participants (n=83) and completed from start of protocol writing to first draft of the clinical study report in just 11 months. This program included all key elements of early drug development in 2 interlinked protocols: the assessment of single and multiple ascending doses, food effect, cardiac safety and proof of concept. The approach described in this article demonstrates how early-phase programs can be designed to be performed, analyzed and reported time- and cost-efficiently.

Adaptive trial designs have the potential to address common challenges in drug development; they decrease timelines and costs of early drug development and efficiently create data that support future trials in target populations. While allowing for flexibility and evolution, adaptive strategies introduce some complexity to the design and implementation of trial protocols. Previously published work by the authors include a retrospective analysis of time savings using adaptive design and a systematic, 3-step methodology for writing early-phase adaptive integrated protocols. This article builds on the authors' published work demonstrating the practical implementation of the adaptive protocol writing methodology and discussing the challenges and efficiencies. It describes the integration of an early development program of OBE022, a novel, oral, selective prostaglandin F2α receptor antagonist, intended as a treatment for preterm labor, using 2 interdependent, adaptive trial protocols. The program consisted of first-in-human single and multiple ascending dose parts with assessments of food effect, cardiac safety, proof of concept, and interactions of OBE022 with 4 standard of care medicines. The manuscript shows how the trials were tailored to OBE022's pharmacokinetic and pharmacodynamic characteristics and its therapeutic indication. The use of 2 large interdependent, adaptive protocols was facilitated by the United Kingdom's (UK's) regulatory environment and its acceptance of a rules-guided progression through the program. Changes to the planned trial conduct could be made without impacting on timelines, because they used predefined adaptive options within their authorized boundaries, and could therefore be made as nonsubstantial amendments. The program was successful and achieved its objectives. It was efficient and fast: it required a small number of participants (n = 83) and completed from start of protocol writing to first draft of the clinical study report in just 11 months. This program included all key elements of early drug development in 2 interlinked protocols: the assessment of single and multiple ascending doses, food effect, cardiac safety and proof of concept. The approach described in this article demonstrates how early-phase programs can be designed to be performed, analyzed and reported time- and cost-efficiently. Trial registration: EudraCT (ref: 2016-001957-42 and 2016-001958-18).

Introduction:

Background. The aim of this pilot study was to evaluate intranasal buserelin for luteal phase support and compare its efficacy with standard vaginal progesterone in IVF/ICSI antagonist cycles. Methods. This is a prospective, randomized, open, parallel group study. Forty patients underwent ovarian hyperstimulation with human menopausal gonadotropin under pituitary inhibition with gonadotropin-releasing hormone antagonist, while ovulation trigger and luteal support were achieved using intranasal GnRH agonist (group A). Twenty patients had their cycle downregulated with buserelin and stimulated with hMG, while ovulation trigger was achieved using 10,000 IU human chorionic gonadotropin with luteal support by intravaginal progesterone (group B). Results. No difference was observed in estradiol levels. Progesterone levels on day 5 were significantly lower in group A. However, significantly higher levels of luteinizing hormone were observed in group A during the entire luteal phase. Pregnancy rates (31.4% versus 22.2%), implantation rates (22% versus 15.4%), and clinical pregnancy rates (25.7% versus 16.7%) were not statistically different between groups, although a trend towards higher rates was observed in group A. No luteal phase lasting less than 10 days was recorded in either group. Conclusion. Intranasal administration of buserelin is effective for providing luteal phase support in IVF/ICSI antagonist protocols.

We present a characterization of the close environment of GRB980425 based on 5-160mic spectro-imaging obtained with Spitzer. The Gamma-Ray Burst GRB980425 occurred in a nearby (z=0.0085) SBc-type dwarf galaxy, at a projected distance of 900pc from an HII region with strong signatures of Wolf-Rayet (WR) stars. While this "WR region" produces less than 5% of the B-band emission of the host, we find that it is responsible for 45+/-10% of the total infrared luminosity, with a maximum contribution reaching 75% at 25-30mic. This atypical property is rarely observed among morphologically-relaxed dwarves, suggesting a strong causal link with the GRB event. The luminosity of the WR region (L_8-1000mic=4.6x10^8 Lsol), the peak of its spectral energy distribution at <~100mic and the presence of highly-ionized emission lines (e.g., [NeIII]) also reveal extremely young (<5Myr) star-forming activity, with a typical time-scale of only 47Myr to double the stellar mass already built. Finally, the mid-IR over B-band luminosity ratio in this region is substantially higher than in star-forming galaxies with similar L_IR, but it is lower than in young dust-enshrouded stellar clusters. Considering the modest obscuration measured from the silicate features (tau_9.7mic ~ 0.015), this suggests that the WR region is dominated by one or several star clusters that have either partly escaped or cleared out their parent molecular cloud. Combined with the properties characterizing the whole population of GRB hosts, our results reinforce the idea that long GRBs mostly happen within or in the vicinity of relatively unobscured galactic regions harboring very recent star formation.

The Taurus-Auriga star-forming complex hosts the only population of T Tauri stars in which an anticorrelation of X-ray activity and rotation period has been observed. We have used XMM-Newton's European Photon Imaging Cameras to perform the most sensitive survey to date of X-ray emission (0.3-10 keV) from young stars in Taurus-Auriga and investigate the dependences of X-ray activity measures -- X-ray luminosity, Lx, its ratio with the stellar luminosity, Lx/Lstar, and the surface-averaged X-ray flux, Fxs -- on rotation period. We tested for differences in the distributions of Lx/Lstar of fast and slow rotators, accretors and non-accretors, and compared the dependence of Lx/Lstar on the ratio of the rotation period and the convective turnover timescale, the Rossby number, with that of late-type main-sequence stars. We found significant anticorrelations of Lx and Fxs with rotation period, but these could be explained by the typically higher stellar luminosity and effective temperature of fast-rotators in Taurus-Auriga and a near-linear dependence of Lx on Lstar. We found no evidence for a dependence of Lx/Lstar on rotation period, but for accretors to have lower Lx/Lstar than non-accretors at all rotation periods. The Rossby numbers of accretors and non-accretors were found to be the same as those of late-type main-sequence stars showing saturated X-ray emission. We conclude that non-accreting T Tauri stars show X-ray activity entirely consistent with the saturated activity of late-type main-sequence stars. Accreting T Tauri stars show lower X-ray activity, which cannot be attributed to their slower rotation.

Objective:The objective was to show the oral alterations due the prematurity and low birthweight and the interceptive and preventive measures indicated. Source of data:Literature review about the subject. Results:The alterations due the prematurity and low birthweight manifest on the enamel and palatum malformation, as well as in the delayed development of the primary and permanent dentitions.These alterations may affect the esthetics and may predispose to dental caries and maloclussion.So, it is necessary the early establishment of preventive and interceptive measures for these children, avoiding future problems. Conclusions:The preventive cares for preterm children are essential for maintain the oral health, allowing proper growth and development of stomatognathic system, being of importance the multiprofessional care.