Dose Finding Using the Biased Coin Up‐and‐Down Design and Isotonic Regression

Stylianou, Mario; Flournoy, Nancy

doi:10.1111/j.0006-341x.2002.00171.x

Cited by 211 publications

(217 citation statements)

References 16 publications

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“…The ED 90 and 95% CI were estimated using two non-parametric methods, the truncated Dixon and Mood method (simple average of Brownlee, Hodges and Rosenblatt) 21 and the isotonic regression method with the pooled-adjacent-violators algorithm (PAVA) approach with linear calibration. 22 The latter was used only to confirm our findings and supplement our results. Patient characteristics and secondary outcomes were presented as median (range) or n (%).…”

Section: A Sample Size and Statistical Analysissupporting

confidence: 59%

Carbetocin at Cesarean delivery for labour arrest: a sequential allocation trial to determine the effective dose

Nguyen-Lu

Carvalho

Farine

et al. 2015

Can J Anesth/J Can Anesth

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Purpose The aim of this study was to estimate the effective dose 90% (ED 90 ) of carbetocin to provide adequate uterine tone at Cesarean delivery (CD) for labour arrest. Methods We conducted a double-blind dose-finding study of carbetocin using a biased-coin up-and-down design in women undergoing CD for labour arrest under epidural anesthesia. Forty healthy term pregnant women who had received at least three hours of oxytocin infusion during labour were recruited for the study. Carbetocin was administered intravenously upon delivery of the anterior shoulder of the fetus. The first patient received 20 lg, and the dose for the subsequent patient was determined according to the response of the previous patient as per the biased-coin allocation scheme using increments or decrements of 20 lg (maximum 140 lg). Uterine tone was assessed by the obstetrician and rated as satisfactory or unsatisfactory throughout the intraoperative period. The primary outcome was satisfactory uterine tone with no need for additional uterotonic drugs intraoperatively. Secondary outcomes included use of additional uterotonic drugs postoperatively in the first 24 hr, estimated blood loss, and adverse effects. Results The ED 90 of carbetocin to produce adequate uterine tone was estimated at 121 lg (95% confidence interval [CI]: 111 to 130; 99% CI: 108 to 133) using the truncated Dixon and Mood (DM) method. The isotonic estimator of ED 90 was 140 lg; however, the observed response rate across all doses was \ 90%. Also, the 95% CI of the DM estimator is likely to have lower than expected coverage, while the 99% CI may have about 90% coverage. Therefore, these results should be interpreted with caution. The overall median (range) estimated blood loss was 1,014 (104-2,436) mL. The overall incidence of hypotension and tachycardia were 45% and 57.5%, respectively. At a dose of 140 lg, the incidence of tachycardia and intraoperative arrhythmias was 76% and 14%, respectively. Conclusion The ED 90 of carbetocin at CD for labour arrest, as determined in our study, should be interpreted with caution since it may be underestimated. This dose is higher than the currently recommended dose of 100 lg at elective CD and should not be used routinely given the uncertainty regarding its efficacy and the high incidence of arrhythmias at higher doses. This trial was registered at ClinicalTrials.gov, number: NCT01725243. RésuméObjectif L'objectif de cette étude était d'estimer la dose efficace à 90 % (DE 90 ) de la carbétocine pour atteindre un tonus utérin adapté lors d'un accouchement par césarienne (AC) pour arrêt de la progression du travail. Méthode Nous avons réalisé une étude de détermination de dose de carbétocine à double insu en nous fondant sur une méthodologie biaisée de pile ou face chez des femmes subissant un AC pour arrêt de progression du travail sous anesthésie péridurale. Quarante femmes enceintes en bonne santé et à terme ayant reçu une perfusion d'oxytocine pendant au moins trois heures pendant le travail obstétrical ont été recrutées p...

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Section: A Sample Size and Statistical Analysissupporting

confidence: 59%

Carbetocin at Cesarean delivery for labour arrest: a sequential allocation trial to determine the effective dose

Nguyen-Lu

Carvalho

Farine

et al. 2015

Can J Anesth/J Can Anesth

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“…Most studies with this approach in anesthesiology study 20-40 patients [21][22][23][24][25][26][27][28][29] .…”

Section: Discussionmentioning

confidence: 99%

Sugammadex ED90 dose to reverse the rocuronium neuromuscular blockade in obese patients

Silva

Matsui

Kim

et al. 2017

Rev. Col. Bras. Cir.

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Objective: to determine the ED90 (minimum effective dose in 90% of patients) of sugammadex for the reversal of rocuronium-induced moderate neuromuscular blockade (NMB) in patients with grade III obesity undergoing bariatric surgery. Methods: we conducted a prospective study with the biased coin up-and-down sequential design. We chosen the following doses: 2.0mg/Kg, 2.2mg/Kg, 2.4mg/Kg, 2.6mg/Kg, 2.8mg/Kg. The complete reversal of rocuronium-induced NMB considered a T4/T1 ratio ≥0.9 as measured by TOF. After induction of general anesthesia and calibration of the peripheral nerve stimulator and accelerometer, we injected rocuronium 0.6mg/kg. We administered propofol and remifentanil by continuous infusion, and intermittent boluses of rocuronium throughout the procedure. Results: we evaluated 31 patients, of whom 26 had displayed successful reversal of the NMB with sugammadex, and failure in five. The mean time to complete moderate NMB reversal was 213 seconds (172-300, median 25-75%). The ED90 of sugammadex calculated by regression was 2.39mg/kg, with a 95% confidence interval of 2.27-2.46 mg/kg. Conclusion: the ED90 of sugammadex in patients with grade III obesity or higher was 2.39mg/kg.

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“…The isotonic regression estimator for the MTD has been proposed by Leung and Wang (2001), Stylianou and Flournoy (2002), Ivanova et al (2003), and Ji et al (2007). In simulations by Ivanova et al, an isotonic regression estimator outperformed both an empirical estimator and a parametric maximum likelihood estimator for the MTD.…”

Section: Isotonic Regression and The Standard Designmentioning

confidence: 99%

Some Notable Properties of the Standard Oncology Phase I Design

Hather

Mackey²

2009

Journal of Biopharmaceutical Statistics

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We identify three properties of the standard oncology phase I trial design or 3 + 3 design.We show that the standard design implicitly uses isotonic regression to estimate a maximum tolerated dose. We next illustrate the relationship between the standard design and a Bayesian design proposed by Ji et al. (2007). A slight modification to this Bayesian design, under a particular model specification, would assign treatments in a manner identical to the standard design. We finally present calculations revealing the behavior of the standard design in a worst case scenario and compare its behavior with other 3 + 3-like designs.

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Dose Finding Using the Biased Coin Up‐and‐Down Design and Isotonic Regression

Cited by 211 publications

References 16 publications

Carbetocin at Cesarean delivery for labour arrest: a sequential allocation trial to determine the effective dose

Carbetocin at Cesarean delivery for labour arrest: a sequential allocation trial to determine the effective dose

Sugammadex ED90 dose to reverse the rocuronium neuromuscular blockade in obese patients

Some Notable Properties of the Standard Oncology Phase I Design

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