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

2018 ◽  
Vol 28 (12) ◽  
pp. 3491-3501
Author(s):  
Xiaoyin F Fan ◽  
Paul Gallo ◽  
Guoqin Su ◽  
Ronald Menton ◽  
Florencia Segal
Keyword(s):  
Adaptive Design ◽  
Safety Margin ◽  
Proof Of Concept ◽  
Operating Characteristics ◽  
Type 1 Error ◽  
Multi Stage ◽  
Power Threshold ◽  
Design Options ◽  
Size Adjustment ◽  
Sample Size Adjustment

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.

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

BMC Nutrition ◽  
2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Matyas Atnafu Alehegn ◽  
Tsegaye Kebede Fanta ◽  
Agumas Fentahun Ayalew
Keyword(s):  
Pregnant Women ◽  
Study Design ◽  
Health Professionals ◽  
Maternal Nutrition ◽  
Addis Ababa ◽  
Nutrition Counseling ◽  
Institutional Barriers ◽  
Size Adjustment ◽  
Sample Size Adjustment ◽  
Pregnant Mothers

Abstract 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.

Alternative models and randomization techniques for Bayesian response-adaptive randomization with binary outcomes

2021 ◽  
pp. 174077452110101
Author(s):  
Jennifer Proper ◽  
John Connett ◽  
Thomas Murray
Keyword(s):  
Logistic Regression ◽  
Sample Size ◽  
Error Rate ◽  
Adaptive Design ◽  
Type I Error ◽  
Probability Model ◽  
Binary Outcomes ◽  
Type I ◽  
Operating Characteristics ◽  
Type I Error Rate

Background: Bayesian response-adaptive designs, which data adaptively alter the allocation ratio in favor of the better performing treatment, are often criticized for engendering a non-trivial probability of a subject imbalance in favor of the inferior treatment, inflating type I error rate, and increasing sample size requirements. The implementation of these designs using the Thompson sampling methods has generally assumed a simple beta-binomial probability model in the literature; however, the effect of these choices on the resulting design operating characteristics relative to other reasonable alternatives has not been fully examined. Motivated by the Advanced R2 Eperfusion STrategies for Refractory Cardiac Arrest trial, we posit that a logistic probability model coupled with an urn or permuted block randomization method will alleviate some of the practical limitations engendered by the conventional implementation of a two-arm Bayesian response-adaptive design with binary outcomes. In this article, we discuss up to what extent this solution works and when it does not. Methods: A computer simulation study was performed to evaluate the relative merits of a Bayesian response-adaptive design for the Advanced R2 Eperfusion STrategies for Refractory Cardiac Arrest trial using the Thompson sampling methods based on a logistic regression probability model coupled with either an urn or permuted block randomization method that limits deviations from the evolving target allocation ratio. The different implementations of the response-adaptive design were evaluated for type I error rate control across various null response rates and power, among other performance metrics. Results: The logistic regression probability model engenders smaller average sample sizes with similar power, better control over type I error rate, and more favorable treatment arm sample size distributions than the conventional beta-binomial probability model, and designs using the alternative randomization methods have a negligible chance of a sample size imbalance in the wrong direction. Conclusion: Pairing the logistic regression probability model with either of the alternative randomization methods results in a much improved response-adaptive design in regard to important operating characteristics, including type I error rate control and the risk of a sample size imbalance in favor of the inferior treatment.

scholarly journals PDCT-01. BIOLOGICAL MEDICINE FOR DIFFUSE INTRINSIC PONTINE GLIOMAS ERADICATION (BIOMEDE): RESULTS OF THE THREE-ARM BIOMARKER-DRIVEN RANDOMIZED TRIAL IN THE FIRST 230 PATIENTS FROM EUROPE AND AUSTRALIA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi183-vi183
Author(s):  
Jacques Grill ◽  
Gwenael Le Teuff ◽  
Karsten Nysom ◽  
Klas Blomgren ◽  
Darren Hargrave ◽  
...  
Keyword(s):  
Disease Progression ◽  
Adaptive Design ◽  
Diagnostic Yield ◽  
Median Number ◽  
Steering Committee ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Primary Objective ◽  
Open Label ◽  
Pten Loss ◽  
Multi Stage

Abstract BACKGROUND Diffuse intrinsic pontine glioma (DIPG) is one of the most devastating brain neoplasms. Despite 50 years of clinical trials, no improvement of survival has been observed and most children die within 2 years of diagnosis. Only radiotherapy transiently controls disease progression. METHODS/AIMS: BIOMEDE was conceived as a randomized multi-arm multi-stage program (drop-the-loser adaptive design). It started with an open-label phase-II trial comparing three drugs (everolimus, dasatinib, erlotinib) combined with irradiation, allocated according to the presence of their specific targets) with a planned sample size of 250 patients. A stereotactic biopsy was performed at diagnosis to centrally confirm the diagnosis of DIPG (presence of histone H3K27M mutation or loss of K27 trimethylation) and assess biomarkers/targets (PTEN-loss, EGFR-overexpression). Targeted therapies were started concomitantly with radiotherapy and were continued until disease progression. The main objective of the study was to compare the efficacy of randomized groups in terms of overall survival (OS). RESULTS At the 3rd interim analysis, based on 193 randomized patients among the 230 study patients, the IDMC concluded that the study was unlikely to meet its primary objective even if 250 patients were randomized. The median OS from the time of randomization was 10.9, 9.5 and 9 months for everolimus, dasatinib and erlotinib, respectively, which is comparable to historical controls. The median number of courses administered was 7, 5.5 and 6 respectively. Treatment was discontinued due to toxicity in 2%, 13%, and 15%, respectively. No biopsy-related death was reported and diagnostic yield was excellent, with only 5 non-informative biopsies. CONCLUSION BIOMEDE shows the feasibility of biologically-driven treatment in DIPG on a large international scale. Based on the better toxicity profile and the slightly better efficacy, although not statistically significant, the steering committee proposed that everolimus should be used as the control arm for the next step, BIOMEDE 2.0.

scholarly journals Numerical simulation of the non-uniform flow in a full-annulus multi-stage axial compressor with the harmonic balance method

2020 ◽  
Vol 12 (3) ◽  
pp. 168781401989721 ◽  
Author(s):  
Haiou Sun ◽  
Meng Wang ◽  
Zhongyi Wang ◽  
Song Wang ◽  
Franco Magagnato
Keyword(s):  
Flow Field ◽  
Harmonic Balance ◽  
Axial Compressor ◽  
Harmonic Balance Method ◽  
Internal Flow ◽  
Uniform Flow ◽  
Experimental Results ◽  
Balance Method ◽  
Operating Characteristics ◽  
Multi Stage

To improve the understanding of unsteady flow in modern advanced axial compressor, unsteady simulations on full-annulus multi-stage axial compressor are carried out with the harmonic balance method. Since the internal flow in turbomachinery is naturally periodic, the harmonic balance method can be used to reduce the computational cost. In order to verify the accuracy of the harmonic balance method, the numerical results are first compared with the experimental results. The results show that the internal flow field and the operating characteristics of the multi-stage axial compressor obtained by the harmonic balance method coincide with the experimental results with the relative error in the range of 3%. Through the analysis of the internal flow field of the axial compressor, it can be found that the airflow in the clearance of adjacent blade rows gradually changes from axisymmetric to non-axisymmetric and then returns to almost completely axisymmetric distribution before the downstream blade inlet, with only a slight non-axisymmetric distribution, which can be ignored. Moreover, the slight non-axisymmetric distribution will continue to accumulate with the development of the flow and, finally, form a distinct circumferential non-uniform flow field in latter stages, which may be the reason why the traditional single-passage numerical method will cause certain errors in multi-stage axial compressor simulations.

A Knowledge-Based Tool for the Selection of Design Options During the Competitive Tendering of Vehicle Systems

Volume 3 ◽  
2004 ◽  
Author(s):  
Clive I. Kerr ◽  
Rajkumar Roy ◽  
Peter J. Sackett
Keyword(s):  
Automotive Industry ◽  
Proof Of Concept ◽  
Competitive Tendering ◽  
Knowledge Based ◽  
Vehicle System ◽  
Tier 1 ◽  
Vehicle Systems ◽  
Design Options ◽  
Selection Of

In the automotive industry the activities of documenting the design options and generating the necessary request for quotations, for Tier 1 system suppliers to be awarded contracts for design and development, is complex and time-consuming since these activities are predominately manual and paper-based. Thus, a knowledge-based tool is being developed to aid the selection of the design options for vehicle systems during competitive tendering. The tool is based on ontologies in order to provide a common and shared definition for the options available for a given vehicle system. An overview of this approach is provided and, as a ‘proof of concept’, a case study involving seating systems is presented. This paper shows, through the seating system case study, how the functionalities and features of a vehicle system can be selected and documented in order to streamline the business process of contracting out product development through the supply chain.

Tappas: An adaptive enrichment phase 3 trial of TRC105 and pazopanib versus pazopanib alone in patients with advanced angiosarcoma (AAS).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS11081-TPS11081 ◽  
Author(s):  
Robin Lewis Jones ◽  
Steven Attia ◽  
Cyrus R. Mehta ◽  
Lingyun Liu ◽  
Kamalesh Kumar Sankhala ◽  
...  
Keyword(s):  
Sample Size ◽  
Adaptive Design ◽  
Single Agent ◽  
The United States ◽  
Phase 3 ◽  
Type 1 Error ◽  
Secondary Endpoints ◽  
Enrichment Design ◽  
Special Protocol

TPS11081 Background: AAS is an aggressive soft tissue sarcoma (STS) of endothelial cell origin with an expected median overall survival of 8-12 months. Pazopanib (P) is approved for treatment of advanced STS following progression on chemotherapy. In a retrospective study of 40 AAS patients treated with single agent P the median PFS was 3.1 months and median OS 9.9 months with no complete responses. Endoglin is an essential angiogenic receptor expressed on AAS that is upregulated following VEGF inhibition, and TRC105, an endoglin antibody, given with P produced durable complete responses in AAS patients with median PFS of 5.6 months in refractory patients including those receiving prior P. The TAPPAS trial is the first randomized Phase 3 trial performed in AAS, and was initiated following protocol assistance from the EMA and Special Protocol Assessment from the FDA. Methods: TAPPAS is a randomized multicenter study of TRC105/P vs P alone in the United States and Europe that is actively enrolling cutaneous and non-cutaneous AAS patients and incorporates an adaptive enrichment design. Key inclusion criteria: 0, 1 or 2 prior lines of therapy, ECOG ≤ 1. Primary endpoint is PFS and secondary endpoints include ORR and OS. The initial sample size of 124 patients, followed until 95 PFS events, provides more than 80% power to detect a hazard ratio of 0.55. At the time of interim analysis, projected to occur upon the occurrence of 40 events in approximately 70 patients, the result will be classified as belonging to either the favorable, promising, enrichment or unfavorable zones, based on conditional power. The sample size and PFS events will be unchanged in the favorable and unfavorable zones, and will be increased to a total of 200 patients followed for 170 PFS events in the promising zone. The trial will enroll 100 additional patients, with cutaneous disease only, in the enrichment zone and will follow them until 110 events are observed in the total cutaneous population. An independent DMC will follow the trial for safety and futility. The adaptive design requires the enrollment of fewer patients, preserves type-1 error, and protects power to detect a clinically meaningful survival benefit. (NCT 02979899). Clinical trial information: NCT02979899.

Combining Proof-of-Concept With Dose-Finding: Utilization of Adaptive Designs in Migraine Clinical Trials

Cephalalgia ◽  
2008 ◽  
Vol 28 (8) ◽  
pp. 805-812 ◽  
Author(s):  
A Sagkriotis ◽  
J Scholpp
Keyword(s):  
Adaptive Design ◽  
Dose Finding ◽  
Phase Iii ◽  
Proof Of Concept ◽  
Trial Duration ◽  
Number Of Patients ◽  
Probability Of Success ◽  
Flexible Designs ◽  
Subsequent Phase ◽  
Phase Iii Studies

There is an obvious need to improve clinical trial designs with respect to efficiency, duration and the number of patients recruited. Adaptive (flexible) designs may be valuable in this respect. We simulated the properties of a two-stage adaptive proof-of-concept and dose-finding trial design in adult migraine patients with moderate to severe headache, with or without aura. We also assessed the usefulness of a combined Bayesian and frequentist approach in the estimation of the probability of success of subsequent Phase III studies. Applying such an innovative approach would result in a reduction of the required sample size by 30 patients and no prolongation of the trial duration. The probability of success in Phase III is > 81%. An innovative adaptive design can facilitate testing of investigational migraine medications by reducing patient numbers and improving predictivity of success in Phase III.

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