Value beyond the P: The case for higher-quality and better-publicized pilot and feasibility trials

Samuel M. Brown; Robert Paine; Michael Lanspa; Michelle Gong

doi:10.1513/AnnalsATS.201901-059PS

Value beyond the P: The case for higher-quality and better-publicized pilot and feasibility trials

Samuel M. Brown, Robert Paine, Michael Lanspa, Michelle Gong

Medicine

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

Original language	English (US)
Pages (from-to)	1230-1233
Number of pages	4
Journal	Annals of the American Thoracic Society
Volume	16
Issue number	10
DOIs	https://doi.org/10.1513/AnnalsATS.201901-059PS
State	Published - Oct 2019

ASJC Scopus subject areas

Pulmonary and Respiratory Medicine

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10.1513/AnnalsATS.201901-059PS

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@article{00b7685f3694470bb54f0523fbf3f520,

title = "Value beyond the P: The case for higher-quality and better-publicized pilot and feasibility trials",

author = "Brown, {Samuel M.} and Robert Paine and Michael Lanspa and Michelle Gong",

note = "Funding Information: “usual care” control) phase 2a study by Morelli and colleagues (11) drew substantial attention to esmolol infusions in sepsis. We and colleagues were not convinced of appropriate event rates and effect estimates, let alone efficacy for mortality. These concerns were driven in part by the extremely high mortality in both control and treatment arms in the Morelli and colleagues trial (12). We thus undertook a feasibility trial that we designed on analogy to the roll-in phase of device trials (ClinicalTrial.gov: NCT02841241) (13). Despite its small size (N = 7), the rigor and granularity of our feasibility trial allowed us to determine that an immediate phase 3 trial was premature. Lower peak infusion rates of esmolol appeared necessary both to avoid intolerance at higher infusion rates (apparently masked in the Morelli and colleagues trial by concomitant administration of levosimendan, a therapy that has subsequently been suggested to have no efficacy and perhaps some harm [14]). In addition, we identified the need to substantially simplify the protocol for multicenter application. Our experience also emphasized to us the importance of placebo control, even if blinding is at best partial, as patients receiving esmolol had the close attention of an experienced clinician-investigator for several hours. The use of a “usual care” control arm allowed the bias from such differential attention to persist. That differential investigator attention in a high-mortality environment could easily explain the potential efficacy signal in the Morelli and colleagues trial, independent of any direct esmolol efficacy. We knew and reported that although none of the seven patients in our pilot study died, our data provided no useful insight into efficacy. This study was funded by departmental research funds and, on a long path to publication, encountered peer reviewers that asked that we make a claim about efficacy.",

year = "2019",

month = oct,

doi = "10.1513/AnnalsATS.201901-059PS",

language = "English (US)",

volume = "16",

pages = "1230--1233",

journal = "Annals of the American Thoracic Society",

issn = "2325-6621",

publisher = "American Thoracic Society",

number = "10",

}

TY - JOUR

T1 - Value beyond the P

T2 - The case for higher-quality and better-publicized pilot and feasibility trials

AU - Brown, Samuel M.

AU - Paine, Robert

AU - Lanspa, Michael

AU - Gong, Michelle

N1 - Funding Information: “usual care” control) phase 2a study by Morelli and colleagues (11) drew substantial attention to esmolol infusions in sepsis. We and colleagues were not convinced of appropriate event rates and effect estimates, let alone efficacy for mortality. These concerns were driven in part by the extremely high mortality in both control and treatment arms in the Morelli and colleagues trial (12). We thus undertook a feasibility trial that we designed on analogy to the roll-in phase of device trials (ClinicalTrial.gov: NCT02841241) (13). Despite its small size (N = 7), the rigor and granularity of our feasibility trial allowed us to determine that an immediate phase 3 trial was premature. Lower peak infusion rates of esmolol appeared necessary both to avoid intolerance at higher infusion rates (apparently masked in the Morelli and colleagues trial by concomitant administration of levosimendan, a therapy that has subsequently been suggested to have no efficacy and perhaps some harm [14]). In addition, we identified the need to substantially simplify the protocol for multicenter application. Our experience also emphasized to us the importance of placebo control, even if blinding is at best partial, as patients receiving esmolol had the close attention of an experienced clinician-investigator for several hours. The use of a “usual care” control arm allowed the bias from such differential attention to persist. That differential investigator attention in a high-mortality environment could easily explain the potential efficacy signal in the Morelli and colleagues trial, independent of any direct esmolol efficacy. We knew and reported that although none of the seven patients in our pilot study died, our data provided no useful insight into efficacy. This study was funded by departmental research funds and, on a long path to publication, encountered peer reviewers that asked that we make a claim about efficacy.

PY - 2019/10

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JO - Annals of the American Thoracic Society

JF - Annals of the American Thoracic Society

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Value beyond the P: The case for higher-quality and better-publicized pilot and feasibility trials

ASJC Scopus subject areas

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