Cargando…
Suboptimal Dosing Parameters as Possible Factors in the Negative Phase III Clinical Trials of Progesterone for Traumatic Brain Injury
To date, outcomes for all Phase III clinical trials for traumatic brain injury (TBI) have been negative. The recent disappointing results of the Progesterone for the Treatment of Traumatic Brain Injury (ProTECT) and Study of a Neuroprotective Agent, Progesterone, in Severe Traumatic Brain Injury (Sy...
Autores principales: | , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Mary Ann Liebert, Inc.
2017
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455214/ https://www.ncbi.nlm.nih.gov/pubmed/26370183 http://dx.doi.org/10.1089/neu.2015.4179 |
_version_ | 1783240999373373440 |
---|---|
author | Howard, Randy B. Sayeed, Iqbal Stein, Donald G. |
author_facet | Howard, Randy B. Sayeed, Iqbal Stein, Donald G. |
author_sort | Howard, Randy B. |
collection | PubMed |
description | To date, outcomes for all Phase III clinical trials for traumatic brain injury (TBI) have been negative. The recent disappointing results of the Progesterone for the Treatment of Traumatic Brain Injury (ProTECT) and Study of a Neuroprotective Agent, Progesterone, in Severe Traumatic Brain Injury (SyNAPSe) Phase III trials for progesterone in TBI have triggered considerable speculation about the reasons for the negative outcomes of these two studies in particular and for those of all previous Phase III TBI clinical trials in general. Among the factors proposed to explain the ProTECT III and SyNAPSe results, the investigators themselves and others have cited: 1) the pathophysiological complexity of TBI itself; 2) issues with the quality and clinical relevance of the preclinical animal models; 3) insufficiently sensitive clinical endpoints; and 4) inappropriate clinical trial designs and strategies. This paper highlights three critical trial design factors that may have contributed substantially to the negative outcomes: 1) suboptimal doses and treatment durations in the Phase II studies; 2) the strategic decision not to perform Phase IIB studies to optimize these variables before initiating Phase III; and 3) the lack of incorporation of the preclinical and Chinese Phase II results, as well as allometric scaling principles, into the Phase III designs. Given these circumstances and the exceptional pleiotropic potential of progesterone as a TBI (and stroke) therapeutic, we are advocating a return to Phase IIB testing. We advocate the incorporation of dose and schedule optimization focused on lower doses and a longer duration of treatment, combined with the addressing of other potential trial design problems raised by the authors in the recently published trial results. |
format | Online Article Text |
id | pubmed-5455214 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Mary Ann Liebert, Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-54552142017-06-06 Suboptimal Dosing Parameters as Possible Factors in the Negative Phase III Clinical Trials of Progesterone for Traumatic Brain Injury Howard, Randy B. Sayeed, Iqbal Stein, Donald G. J Neurotrauma Review To date, outcomes for all Phase III clinical trials for traumatic brain injury (TBI) have been negative. The recent disappointing results of the Progesterone for the Treatment of Traumatic Brain Injury (ProTECT) and Study of a Neuroprotective Agent, Progesterone, in Severe Traumatic Brain Injury (SyNAPSe) Phase III trials for progesterone in TBI have triggered considerable speculation about the reasons for the negative outcomes of these two studies in particular and for those of all previous Phase III TBI clinical trials in general. Among the factors proposed to explain the ProTECT III and SyNAPSe results, the investigators themselves and others have cited: 1) the pathophysiological complexity of TBI itself; 2) issues with the quality and clinical relevance of the preclinical animal models; 3) insufficiently sensitive clinical endpoints; and 4) inappropriate clinical trial designs and strategies. This paper highlights three critical trial design factors that may have contributed substantially to the negative outcomes: 1) suboptimal doses and treatment durations in the Phase II studies; 2) the strategic decision not to perform Phase IIB studies to optimize these variables before initiating Phase III; and 3) the lack of incorporation of the preclinical and Chinese Phase II results, as well as allometric scaling principles, into the Phase III designs. Given these circumstances and the exceptional pleiotropic potential of progesterone as a TBI (and stroke) therapeutic, we are advocating a return to Phase IIB testing. We advocate the incorporation of dose and schedule optimization focused on lower doses and a longer duration of treatment, combined with the addressing of other potential trial design problems raised by the authors in the recently published trial results. Mary Ann Liebert, Inc. 2017-06-01 2017-06-01 /pmc/articles/PMC5455214/ /pubmed/26370183 http://dx.doi.org/10.1089/neu.2015.4179 Text en © Randy B. Howard, Iqbal Sayeed, Donald G. Stein, 2015; Published by Mary Ann Liebert, Inc. This Open Access article is distributed under the terms of the Creative Commons Attribution Noncommercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited. |
spellingShingle | Review Howard, Randy B. Sayeed, Iqbal Stein, Donald G. Suboptimal Dosing Parameters as Possible Factors in the Negative Phase III Clinical Trials of Progesterone for Traumatic Brain Injury |
title | Suboptimal Dosing Parameters as Possible Factors in the Negative Phase III Clinical Trials of Progesterone for Traumatic Brain Injury |
title_full | Suboptimal Dosing Parameters as Possible Factors in the Negative Phase III Clinical Trials of Progesterone for Traumatic Brain Injury |
title_fullStr | Suboptimal Dosing Parameters as Possible Factors in the Negative Phase III Clinical Trials of Progesterone for Traumatic Brain Injury |
title_full_unstemmed | Suboptimal Dosing Parameters as Possible Factors in the Negative Phase III Clinical Trials of Progesterone for Traumatic Brain Injury |
title_short | Suboptimal Dosing Parameters as Possible Factors in the Negative Phase III Clinical Trials of Progesterone for Traumatic Brain Injury |
title_sort | suboptimal dosing parameters as possible factors in the negative phase iii clinical trials of progesterone for traumatic brain injury |
topic | Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455214/ https://www.ncbi.nlm.nih.gov/pubmed/26370183 http://dx.doi.org/10.1089/neu.2015.4179 |
work_keys_str_mv | AT howardrandyb suboptimaldosingparametersaspossiblefactorsinthenegativephaseiiiclinicaltrialsofprogesteronefortraumaticbraininjury AT sayeediqbal suboptimaldosingparametersaspossiblefactorsinthenegativephaseiiiclinicaltrialsofprogesteronefortraumaticbraininjury AT steindonaldg suboptimaldosingparametersaspossiblefactorsinthenegativephaseiiiclinicaltrialsofprogesteronefortraumaticbraininjury |