The practical application of adaptive study design in early phase clinical trials: a retrospective analysis of time savings

Lorch, Ulrike; Berelowitz, K.; Özen, Cihan; Naseem, Asif; Akuffo, E.; Täubel, Jörg

doi:10.1007/s00228-011-1176-3

Cited by 15 publications

(10 citation statements)

References 3 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This was a randomized, double-blind, placebo and positivecontrolled, four-way crossover study using features of an adaptive study design, including the potential to add subjects depending on the standard deviation obtained during a blinded ECG review allowing the sample size to be adapted optimally to the variability occurring in this particular trial [21]. The 40 eligible subjects were randomized to one of four sequences of the four study treatments ( Figure 1): oral moxifloxacin 400 mg (M), i.v.…”

Section: Methodsmentioning

confidence: 99%

Thorough QT study of the effect of intravenous amisulpride on QTc interval in Caucasian and Japanese healthy subjects

Täubel

Ferber

Fox

et al. 2016

Brit J Clinical Pharma

View full text Add to dashboard Cite

AimThe D2/D3 antagonist amisulpride has shown promising efficacy against postoperative nausea and vomiting (PONV) at low doses. We investigated whether intravenous amisulpride has an effect on the QTc interval in a formal Thorough QT study (TQT).MethodsThis was a randomized, double‐blind, placebo and positive‐controlled, four‐way crossover study. Forty healthy Caucasian and Japanese subjects were included to receive a single administration of 5 mg and 40 mg of i.v. amisulpride or a single oral dose of moxifloxacin or placebo per period.ResultsThe therapeutic dose of 5 mg amisulpride was associated with a slight, transient increase in mean ΔΔQTcF, from 2.0 ms prior to dosing to a peak of 5 ms (90% CI: 2.8, 7.1 ms) at 8 min, decreasing to 2.1 ms at 30 min after dosing. The supra‐therapeutic dose of 40 mg given at twice the infusion rate was associated with prolongation in ΔΔQTcF peaking at 23.4 ms (90% CI: 21.3, 25.5 ms) at the end of infusion (8 min), returning below 10 ms within 1.5 h. Assay sensitivity was confirmed; ΔΔQTcF had increased by 12.3 ms (90% CI 10.1, 14.6 ms) at 4 h post‐dose. The PK‐PD relationship revealed no differences between Caucasian and Japanese subjects (p‐value > 0.5).ConclusionsAmisulpride has a plasma concentration‐dependent effect on the QTc interval. The proposed therapeutic dose for management of PONV does not lead to a prolongation of QTcF above the threshold of regulatory concern, while such effect could not be excluded for the supratherapeutic dose.

show abstract

Section: Methodsmentioning

confidence: 99%

Thorough QT study of the effect of intravenous amisulpride on QTc interval in Caucasian and Japanese healthy subjects

Täubel

Ferber

Fox

et al. 2016

Brit J Clinical Pharma

View full text Add to dashboard Cite

show abstract

“…The flexibility to make mid-course adaptations to a trial is not a virtue in itself but rather a gateway to more efficient trials [ 20 ] that should also be more appealing from a patient’s perspective in comparison to non-ADs because: Recruitment to futile treatment arms may stop early. Fewer patients may be randomised to a less promising treatment or dose.…”

Section: Why What and When To Adapt In Clinical Trialsmentioning

confidence: 99%

Adaptive designs in clinical trials: why use them, and how to run and report them

Pallmann

Bedding

Choodari‐Oskooei

et al. 2018

BMC Med

527

449

View full text Add to dashboard Cite

Adaptive designs can make clinical trials more flexible by utilising results accumulating in the trial to modify the trial’s course in accordance with pre-specified rules. Trials with an adaptive design are often more efficient, informative and ethical than trials with a traditional fixed design since they often make better use of resources such as time and money, and might require fewer participants. Adaptive designs can be applied across all phases of clinical research, from early-phase dose escalation to confirmatory trials. The pace of the uptake of adaptive designs in clinical research, however, has remained well behind that of the statistical literature introducing new methods and highlighting their potential advantages. We speculate that one factor contributing to this is that the full range of adaptations available to trial designs, as well as their goals, advantages and limitations, remains unfamiliar to many parts of the clinical community. Additionally, the term adaptive design has been misleadingly used as an all-encompassing label to refer to certain methods that could be deemed controversial or that have been inadequately implemented.We believe that even if the planning and analysis of a trial is undertaken by an expert statistician, it is essential that the investigators understand the implications of using an adaptive design, for example, what the practical challenges are, what can (and cannot) be inferred from the results of such a trial, and how to report and communicate the results. This tutorial paper provides guidance on key aspects of adaptive designs that are relevant to clinical triallists. We explain the basic rationale behind adaptive designs, clarify ambiguous terminology and summarise the utility and pitfalls of adaptive designs. We discuss practical aspects around funding, ethical approval, treatment supply and communication with stakeholders and trial participants. Our focus, however, is on the interpretation and reporting of results from adaptive design trials, which we consider vital for anyone involved in medical research. We emphasise the general principles of transparency and reproducibility and suggest how best to put them into practice.

show abstract

“…The flexibility and time savings [11] of an adaptive design may be lost if interim data at decision making time points and proposed adaptive changes need to be disseminated to or authorised by the CA or REC. The UK has a favourable environment for the conduct of adaptive studies.…”

Section: Discussionmentioning

confidence: 99%

Three steps to writing adaptive study protocols in the early phase clinical development of new medicines

Lorch

O'Kane²,

Täubel

2014

BMC Med Res Methodol

View full text Add to dashboard Cite

This article attempts to define terminology and to describe a process for writing adaptive, early phase study protocols which are transparent, self-intuitive and uniform. It provides a step by step guide, giving templates from projects which received regulatory authorisation and were successfully performed in the UK. During adaptive studies evolving data is used to modify the trial design and conduct within the protocol-defined remit. Adaptations within that remit are documented using non-substantial protocol amendments which do not require regulatory or ethical review. This concept is efficient in gathering relevant data in exploratory early phase studies, ethical and time- and cost-effective.

show abstract

The practical application of adaptive study design in early phase clinical trials: a retrospective analysis of time savings

Abstract: We conclude that the use of adaptive study design saves time in early phase research programs. This is achieved by abolishing the need for substantial amendments or by mitigating their impact on timelines and by using adaptive scheduling efficiencies.

Cited by 15 publications

References 3 publications

Thorough QT study of the effect of intravenous amisulpride on QTc interval in Caucasian and Japanese healthy subjects

Thorough QT study of the effect of intravenous amisulpride on QTc interval in Caucasian and Japanese healthy subjects

Adaptive designs in clinical trials: why use them, and how to run and report them

Three steps to writing adaptive study protocols in the early phase clinical development of new medicines

Contact Info

Product

Resources

About