Adaptive study design to assess effect of TRPV4 inhibition in patients with chronic cough

ObjectiveAirway sensory nerves involved in the cough reflex are activated by adenosine triphosphate (ATP) agonism of P2X purinoceptor 3 (P2X3) receptors. Transient receptor potential vanilloid 4 (TRPV4) channel activation causes ATP release from airway cells and it is hypothesised that a TRPV4-ATP-P2X3 axis contributes to chronic cough. An adaptive study was run to determine if TRPV4 inhibition, using the selective TRPV4 channel blocker GSK2798745, was effective in reducing cough.MethodsA two-period randomised, double blinded, placebo-controlled crossover study was designed with interim analyses for futility and sample size adjustment. Refractory chronic cough patients received either GSK2798745 or placebo once daily for 7 days with a wash-out between treatments. PK samples were collected for analysis of GSK2798745 at end of study. The primary endpoint was total cough counts assessed objectively during day-time hours (10 h) following 7 days of dosing.ResultsInterim analysis was performed after 12 participants completed both treatment periods. This showed a 32% increase in cough counts on Day 7 for GSK2798745 compared to placebo; the pre-defined negative criteria for the study were met and the study was stopped. At this point 17 participants had been enrolled (Mean 61yrs; 88% female), and 15 had completed the study. Final study results for posterior median cough counts showed a 34% (90% CrI: −3%, +85%) numerical increase for GSK2798745 compared to placebo.ConclusionThere was no evidence of an anti-tussive effect of GSK2798745. The study design allowed the decision on lack of efficacy to be made with minimal participant exposure to the investigational drug.

Exploring maternal nutrition counseling provided by health professionals during antenatal care follow-up: a qualitative study in Addis Ababa, Ethiopia-2019

Background Nutritional awareness and practice of women during pregnancy could be determining their nutritional status, which significantly affects the outcome of pregnancy. Therefore this study aims to explore the maternal nutrition counseling provided by health professionals for pregnant women, Barriers to maternal nutrition, and major interventions. Methods A descriptive study design with a qualitative method by using ground theory tradition, based on constructivist research approach and Charmaz’s (2000) study design has been conducted from September-01/2019 _November-16/2019 among pregnant women who got ANC service in Addis Ababa, Ethiopia. A purposive sampling technique was used. Practical observations and in-depth interviews were conducted. The sample size adjustment has been carried out according to the information saturation obtained, and finally, 81 practical observations, In-depth interview with two center managers, nine health professionals and eleven term pregnant women has been conducted. An observational checklist and Semi-structured, open-ended questionnaires were used. Data, the environment, and methodological triangulation were carried out. A conceptual framework has been established based on the data collected about the whole process of maternal nutrition counseling during pregnancy. ATLAS TI software was utilized for information analysis. The results Most participants responded that maternal nutrition counseling provided to pregnant mothers is not adequate and neglected by most stakeholders. From 81 practical observations, health professionals counseled to mothers were 10 what to feed, 4 what to limit to consume, and 5 were counseled about what to eat during pregnancy. Close to all the respondents agreed on the importance of providing nutrition counseled by the nutritionists. Most of the study participants emphasized a shortage of time as primary barriers. Institutional Barriers, Professional Barriers, Maternal Barriers, and Community Barriers were major barriers to nutrition counseling. Conclusions Generally, maternal nutrition counseling provided to pregnant mothers was not adequate and neglected by most stakeholders. Shortage of time due to client flow, Institutional Barriers, Professional Barriers, Maternal Barriers, and Community Barriers were major categories of maternal nutritional counseling barriers. Information update and timely preparation were recommended to health professionals.

A proof-of-concept-to-confirmatory multiple adaptation design in the development of an anti-viral treatment

In the clinical development of some new infectious disease drugs, early clinical pharmacology trials may predict with high confidence that the efficacious doses are well below the range of the safety margin. In this case, a dose-ranging study may be unnecessary after a proof-of-concept (PoC) study testing the highest dose. A multi-stage adaptive design spanning both PoC and confirmatory stages is proposed in this context. The design incorporates two interim analyses allowing strategies for stopping, continuing, or expanding the study. A conditional power threshold for a binary endpoint is proposed to assess futility. Additional components of early efficacy and sample size adjustment are also included to enhance the design's flexibility and robustness. Design operating characteristics are evaluated by numerical calculation. We show that the proposed streamlined trial design has the same statistical rigor as a conventional phase 3 clinical trial with adequate power and a properly controlled type 1 error rate. Additional adaptive design options are also investigated and discussed.

Evaluation of Performance of Adaptive Designs Based on Treatment Effect Intervals

The accuracy of the treatment effect estimation is crucial to the success of Phase 3 studies. The calculation of sample size relies on the treatment effect estimation and cannot be changed during the trial in a fixed sample size design. Oftentimes, with limited efficacy data available from early phase studies and relevant historical studies, the sample size calculation may not accurately reflect the true treatment effect. Several adaptive designs have been proposed to address this uncertainty in the sample size calculation. These adaptive designs provide flexibility of sample size adjustment during the trial by allowing early trial stopping or sample size adjustment at interim look(s). The use of adaptive designs can optimize the trial performance when the treatment effect is an assumed constant value. However in practice, it may be more reasonable to consider the treatment effect within an interval rather than as a point estimate. Because proper selection of adaptive designs may decrease the failure rate of Phase 3 clinical trials and increase the chance for new drug approval, this paper proposes measures and evaluates the performance of different adaptive designs based on treatment effect intervals, and identifies factors that may affect the performance of adaptive designs.

A Dynamic State-Space Model of Coded Political Texts

This article presents a new method of reconstructing actors' political positions from coded political texts. It is based on a model that combines a dynamic perspective on actors' political positions with a probabilistic account of how these positions are translated into emphases of policy topics in political texts. In the article it is shown how model parameters can be estimated based on a maximum marginal likelihood principle and how political actors' positions can be reconstructed using empirical Bayes techniques. For this purpose, a Monte Carlo Expectation Maximization algorithm is used that employs independent sample techniques with automatic Monte Carlo sample size adjustment. An example application is given by estimating a model of an economic policy space and a noneconomic policy space based on the data from the Comparative Manifesto Project. Parties' positions in policy spaces reconstructed using these models are made publicly available for download.