Model-Based Bayesian Adaptive Dose-Finding Designs for a Phase II Trial

2011 ◽  
Vol 3 (2) ◽  
pp. 276-287 ◽  
Author(s):  
Byron Jones ◽  
Gary Layton ◽  
Helen Richardson ◽  
Neal Thomas
Keyword(s):  
Phase Ii ◽  
Phase Ii Trial ◽  
Dose Finding ◽  
Model Based

scholarly journals Levetiracetam optimal dose-finding as first-line treatment for neonatal seizures occurring in the context of hypoxic-ischaemic encephalopathy (LEVNEONAT-1): study protocol of a phase II trial

BMJ Open ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. e022739 ◽  
Author(s):  
Geraldine Favrais ◽  
Moreno Ursino ◽  
Catherine Mouchel ◽  
Estelle Boivin ◽  
Vincent Jullien ◽  
...  
Keyword(s):  
Dose Level ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Optimal Dose ◽  
Dose Finding ◽  
Loading Dose ◽  
Line Treatment ◽  
Neonatal Seizures ◽  
First Line ◽  
First Line Treatment

IntroductionTherapeutic schedules for treating neonatal seizures remain elusive. First-line treatment with phenobarbital is widely supported but without strong scientific evidence. Levetiracetam (LEV) is an emerging and promising antiepileptic drug (AED). The aim of this phase II trial is to determine the benefits of LEV by applying a strict methodology and to estimate the optimal dose of LEV as a first-line AED to treat seizures in newborns suffering from hypoxic-ischaemic encephalopathy.Methods and analysisLEVNEONAT-1 is an open and sequential LEV dose-finding study. The optimal dose is that which is estimated to be associated with a toxicity not exceeding 10% and an efficacy higher than 60%. Efficacy is defined by a seizure burden reduction of 80% after the loading dose. Four increasing dose regimens will be assessed including one loading dose of 30, 40, 50 or 60 mg/kg followed by eight maintenance doses (ie, a quarter of the loading dose) injected every 8 hours. A two-patient cohort will be necessary at each dose level to consider an upper dose level assignment. The maximal sample size expected is 50 participants with a minimum of 24 patients or fewer in the case of a high rate of toxicity. Patients will be recruited in five neonatal intensive care units beginning in October 2017 and continuing for 2 years. In parallel, the LEV pharmacokinetics will be measured five times (ie, 30 min; 4 and 7 hours after the loading dose; 1–3 hours and 12–18 hours after the last maintenance dose).Ethics and disseminationEthics approval has been obtained from the regional ethical committee (2016-R25) and the French Drug Safety Agency (160652A-31). The results will be published in a peer-reviewed journal. The results will also be presented at medical meetings.Trial registration numberNCT02229123; Pre-results.

Bone mineral density changes following discontinuation of ronacaleret treatment: Off-treatment extension of a randomized, dose-finding phase II trial

Bone ◽  
2014 ◽  
Vol 67 ◽  
pp. 104-108 ◽  
Author(s):  
Lorraine A. Fitzpatrick ◽  
Margaret Wooddell ◽  
Christine E. Dabrowski ◽  
Gregory Cicconetti ◽  
David N. Gordon
Keyword(s):  
Bone Mineral Density ◽  
Bone Mineral ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Dose Finding ◽  
Mineral Density

scholarly journals TRAFIC: Statistical Plan for a Pragmatic Early Phase 1/2 Bayesian Adaptive Dose Escalation Trial in Rheumatoid Arthritis

2021 ◽  
Author(s):  
Michael Cole ◽  
Christina Yap ◽  
Christopher Buckley ◽  
Wan-Fai Ng ◽  
Iain McInnes ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Decision Making ◽  
Phase I ◽  
Phase Ii ◽  
Early Phase ◽  
Phase I Trial ◽  
Dose Finding ◽  
Model Parameters ◽  
Model Based ◽  
Transition Pathways

Abstract Background: Adaptive model-based dose-finding designs have demonstrated advantages over traditional rule-based designs but have increased statistical complexity resulting in slow uptake especially outside of cancer trials. TRAFIC is a multi-centre, early phase trial in Rheumatoid Arthritis incorporating a model-based design.Methods: A Bayesian adaptive dose-finding phase I trial rolling into a single arm, single stage phase II trial. Model parameters for phase I were chosen via Monte Carlo simulation evaluating objective performance measures under clinically relevant scenarios and incorporated stopping rules for early termination. Potential designs were further calibrated utilising dose transition pathways.Discussion: TRAFIC is an MRC funded trial of a re-purposed treatment demonstrating that it is possible to design, fund and implement a model-based phase I trial in a non-cancer population within conventional research funding tracks and regulatory constraints. The phase I design allows borrowing of information from previous trials; all accumulated data to be utilised in decision-making; verification of operating characteristics through simulation; improved understanding for management and oversight teams through dose transition pathways. The rolling phase II design brings efficiencies in trial conduct including site and monitoring activities, and cost.TRAFIC is the first funded model-based dose-finding trial in inflammatory disease demonstrating that small phase I/II trials can have an underlying statistical basis for decision-making and interpretation.Trial Registration: ISRCTN 36667085

scholarly journals A double-blinded randomised placebo-controlled phase II trial to evaluate high dose rifampicin for tuberculous meningitis: a dose finding study

2018 ◽  
Author(s):  
S Dian ◽  
V Yunivita ◽  
AR Ganiem ◽  
T Pramaesya ◽  
L Chaidir ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase Ii ◽  
Tuberculous Meningitis ◽  
Phase Ii Trial ◽  
Standard Dose ◽  
Geometric Mean ◽  
Dose Finding ◽  
Phase Iii ◽  
High Dose ◽  
Double Blinded

ABSTRACTBackgroundHigh doses of rifampicin may help tuberculous meningitis (TBM) patients to survive. Pharmacokinetic-pharmacodynamic evaluations suggested that rifampicin doses higher than 13 mg/kg intravenously or 20 mg/kg orally (as previously studied) are warranted to maximize treatment response.MethodsIn a double-blinded, randomised, placebo-controlled phase II trial, we assigned 60 adult TBM patients in Bandung, Indonesia, to standard 450 mg, 900 mg or 1350 mg (10, 20 and 30 mg/kg) oral rifampicin combined with other TB drugs for 30 days. Endpoints included pharmacokinetic measures, adverse events and survival.ResultsA double and triple dose of oral rifampicin led to three and five-fold higher geometric mean total exposures in plasma in the critical early days (2±1) of treatment (AUC0-24h: 53·5 mg.h/L vs 170·6 mg.h/L vs. 293·5 mg.h/L, p<0·001), with proportional increases in CSF concentrations and without an increase in the incidence of grade 3/4 adverse events. Six-month mortality was 7/20 (35%, 9/20 (45%) and 3/20 (15%) in the 10, 20 and 30 mg/kg groups, respectively (p=0·12).ConclusionsTripling the standard dose caused a large increase in rifampicin exposure in plasma and CSF and was safe. Survival benefit with this dose should now be evaluated in a larger phase III clinical trial.

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