Accepted Manuscript Placebo-Controlled Feasibility Randomized Trial? Álvaro Sanz Rubiales , MD, PhD María Luisa del Valle , MD, PhD PII:

S0885-3924(14)00251-6

DOI:

10.1016/j.jpainsymman.2014.03.011

Reference:

JPS 8669

To appear in:

Journal of Pain and Symptom Management

Received Date: 13 March 2014 Accepted Date: 23 March 2014

Please cite this article as: Rubiales ÁS, del Valle ML, Placebo-Controlled Feasibility Randomized Trial?, Journal of Pain and Symptom Management (2014), doi: 10.1016/j.jpainsymman.2014.03.011. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT

Letter to the Editor

14-00115

Placebo-Controlled Feasibility Randomized Trial? To the Editor:

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The design of the trial that studied the effects of prophylactic subcutaneous fentanyl on exercise-induced breakthrough dyspnea in cancer patients was surprising (1). The authors

designed a double-blind, randomized, parallel, and placebo-controlled trial to examine the effect

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of subcutaneous fentanyl on dyspnea in a before and after comparison. Any controlled trial should include a control group to compare with an experimental group; however, this placebo-

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controlled trial did not directly compare the results between subcutaneous fentanyl and placebo to show whether fentanyl was or was not better than placebo. It was designed to examine only within-arm effects: the aim of the placebo arm was to examine the magnitude of placebo effect. The trial probably should have been presented as a randomized phase II trial where both arms are

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analyzed independently (2). The conclusions of the trial were that prophylactic fentanyl improved dyspnea, fatigue, walk distance, and respiratory rate, and the authors observed a large placebo effect, without any reference to the differences between fentanyl and placebo.

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The primary objective of the trial was not to examine or compare the effect of subcutaneous fentanyl or placebo; its primary aim was to determine the feasibility of conducting

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a randomized trial of subcutaneous fentanyl and placebo. As a feasibility study, it was focused on the processes of the main study to ensure recruitment, randomization, treatment, and followup assessments were all performed adequately (3). The study was done with a small number of patients and was under-powered; it was done to justify a subsequent adequately powered randomized controlled trial. It is generally accepted that small, underpowered clinical trials may be ethically questionable and participants in such studies should be informed that they are in a

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pilot study and that there may not be a further larger study (3). We wonder if patients entering the trial were really aware of the objectives, if they knew that they were participating in a feasibility study, and if they knew that, if they were assigned to the placebo arm, the effect of the

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placebo would not be compared with the experimental arm.

Álvaro Sanz Rubiales, MD, PhD

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Medical Oncology Section

Valladolid, Spain E-mail: [email protected]

María Luisa del Valle, MD, PhD

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Radiotherapy Service

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Hospital Universitario del Río Hortega

Hospital Clínico Universitario de Valladolid

References

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Valladolid, Spain

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1. Hui D, Xu A, Frisbee-Hume S, et al. Effects of prophylactic subcutaneous fentanyl on exercise-induced breakthrough dyspnea in cancer patients: a preliminary double-blind, randomized, controlled trial. J Pain Symptom Manage 2014;47:209-217. 2. Rubiales AS, del Valle ML. Randomized phase II trials in lung cancer. [Letter]. Ann Oncol 1996;7:755.

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3. Arain M, Campbell MJ, Cooper Cl, Lancaster GA. What is a pilot or feasibility study? A

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review of current practice and editorial policy. BMC Med Res Methodol 2010;10:67.

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