Abstract
This paper proposes randomized controlled clinical trial design to evaluate external cooling as a means to control fever and thereby reduce mortality in patients with septic shock. The trial will include concurrent external cooling and control arms while adaptively incorporating historical control arm data. Bayesian group sequential monitoring will be done using a posterior comparative test based on the 60-day survival distribution in each concurrent arm. Posterior inference will follow from a Bayesian discrete time survival model that facilitates adaptive incorporation of the historical control data through an innovative regression framework with a multivariate spike-and-slab prior distribution on the historical bias parameters. For each interim test, the amount of information borrowed from the historical control data will be determined adaptively in a manner that reflects the degree of agreement between historical and concurrent control arm data. Guidance is provided for selecting Bayesian posterior probability group-sequential monitoring boundaries. Simulation results elucidating how the proposed method borrows strength from the historical control data are reported. In the absence of historical control arm bias, the proposed design controls the type I error rate and provides substantially larger power than reasonable comparators, whereas in the presence bias of varying magnitude, type I error rate inflation is curbed.
Highlights
The methodology described in this paper was motivated by the problem of designing a randomized controlled trial to evaluate the effectiveness of using external cooling to con-U1083, Universite Angers, UBL, Angers, FranceInserm, Centre de Recherche des Cordeliers, Sorbonne Universite, Universite de Paris, Paris, France ∗∗CIC-EC 1418 Inserm, Hopital Europeen Georges-Pompidou, Paris, France ††Funded in part by NIH/NCI Grant P30-CA077598
A randomized controlled trial reported by Asfar et al (2014) comparing the target ranges 80–85 versus 65–70 mm Hg for mean arterial pressure (MAP) in septic shock patients with a history of hypertension admitted to an intensive care unit (ICU) found no significant difference in either 28-day or 90-day mortality rates
We have proposed and investigated the operating characteristics of a Bayesian group sequential design for a randomized controlled trial to assess the effectiveness of using external cooling to control fever in patients with septic shock admitted to an ICU
Summary
The methodology described in this paper was motivated by the problem of designing a randomized controlled trial to evaluate the effectiveness of using external cooling to con-U1083, Universite Angers, UBL, Angers, FranceInserm, Centre de Recherche des Cordeliers, Sorbonne Universite, Universite de Paris, Paris, France ∗∗CIC-EC 1418 Inserm, Hopital Europeen Georges-Pompidou, Paris, France ††Funded in part by NIH/NCI Grant P30-CA077598. SepsisCool Design trol fever and thereby reduce mortality in patients with septic shock admitted to a hospital intensive care unit (ICU). The 60-day mortality rate for patients with septic shock admitted to an ICU is about 40% (Annane et al, 2003; Caironi et al, 2014; Asfar et al, 2014). Standard ICU treatment for septic shock may involve antibiotics or surgery for infection, infusion of fluids, and a vasopressor to maintain the patient’s mean arterial pressure (MAP) at a minimal level to sustain organ function (Dellinger et al, 2013). A randomized controlled trial reported by Asfar et al (2014) comparing the target ranges 80–85 versus 65–70 mm Hg for MAP in septic shock patients with a history of hypertension admitted to an ICU found no significant difference in either 28-day or 90-day mortality rates. While the target MAP range will not be the focus of the trial described in this paper, the trial reported by Asfar et al (2014) is our source for historical control data
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