MedicalResearch.com Interview with:
Dr. Brett E. Skolnick PhD
Department of Neurosurgery
Cushing Neuroscience Institute
Hofstra North Shore–LIJ School of Medicine, Manhasset, NY
Medical Research: What is the background for this study? What are the main findings?
Dr. Skolnick: The experimental evidence for a role of progesterone is based on extensive non-clinical studies in non-primate species (4 animal species such as rat, mice) the majority of which indicate that progesterone has a variety of neuroprotective properties. The animal models of injury in traumatic brain injury (TBI) have included models of blunt trauma, fluid percussion injury, cortical aspiration but similar effects have been seen stroke models and models of spinal cord injury. In these experiments progesterone has been shown to reduce cerebral edema thus limiting the effects or preventing intracranial pressure increases which can lead to secondary injury. Progesterone has also been shown to exert anti-inflammatory, anti-apopotic and perhaps even anti-oxidant effects. All of these effect are postulated to work synergistically to prevent cell death which could result in improved functional outcomes.
Two small single center clinical trials provided the support in traumatic brain injury patients that progesterone could have impact on functional outcomes in larger, properly powered trials. The results of which are summarized in the NEJM article.
In the current trial evaluated the Glasgow Outcome Scale and the extended version of the Glasgow Outcome scale at 6 months following injury. These scales are well validated scales that are used to determine the degree of recovery in terms of disability and handicap due to TBI rather than the degree of impairment. The GOS has 5 levels: death, vegetative state, severe disability, moderate disability and good recovery with death and vegetative state typically collapsed because they are considered equally undesirable. The Extended GOS takes the three best levels of recovery and subdivides these into a upper and lower category to increase the granularity of the outcome measure. Progesterone was administered within 8 hour of injury (loading dose followed by continuous infusions) for a total of 120 hours. Careful assessments were performed to ensure optimal patient management during the trial to provide the best background to evaluate the impact of the addition of progesterone or placebo (1 to 1 randomization). No effect was seen on the GOS or the extended GOS. In addition a fairly new approach of categorizing patients based on prognostic factors known at time of randomization (such as Age, baseline GCS, pupillary response, hypoxia, hypotension, Marshall Classification or presence/absence of subarachnoid hemorrhage) as developed by Hukkelhoven and colleagues was used. This was expected to tease out improvements, if they existed in subgroups of patients where perhaps progesterone could work better in the most severe or less severe traumatic brain injury patients. But again no effects were seen. The unfavorable outcomes (see NEJM paper for details) were essentially identical between progesterone and placebo groups whether they had the worst prognosis or the best prognosis.
Medical Research: What should clinicians and patients take away from your report?
Dr. Skolnick: There is little clinical impact to the practice of medicine of the demonstration of the non-beneficial effect of progesterone from these trials (see Wright et al). I say this because progesterone has never had approval for use in traumatic brain injury and as such there is virtually no clinical use ongoing to my knowledge. If physicians were considering the use of progesterone these two studies should firmly establish that progesterone has no positive benefit in severe traumatic brain injury, at least as characterized in the current study populations where GCS <8 (or <12 for Wright et al) with CT evidence, by the Marshall classification, of visible pathology are considered.
Medical Research: What recommendations do you have for future research as a result of this study?
Dr. Skolnick: My personal recommendations are that we should focus attention on determining if there are meanful ways to further differentiate traumatic brain injury into more refined characteristics that could complement the traditional measures (such as GCS score, Marshall Classification) that may provide for meaningful opportunities to intervene with specific therapeutics that could ultimately improve outcomes. In an unrelated series of trials, while at Novo Nordisk, we tried to determine whether recombinant Factor VIIa (NovoSeven) could play a role in the hemorrhage component of traumatic brain injury. In that case we were able to show that rFVIIa did decrease hemorrhage expansion in acute intracerebral hemorrhage but unfortunately this did not translate into clinical benefit in the large phase 3 trial (NEJM, Mayer, et al., 2008, Unfortunately development for non-hemophilia indications was discontinued and no definitive trials were performed on this component of TBI. (see Efficacy and Safety of Recombinant Activated Factor VII for Acute Intracerebral Hemorrhage, 2008, Mayer, S.A. Et al., 358:2127-37.) So it is my hope that we can try to focus in on individual components of injury and then ultimately develop a multi-therapeutic approach for treatment of the traumatic brain injury patient. An ever pressing problem both for our wounded warriors as well as for our global population
Brett E. Skolnick, Ph.D., Andrew I. Maas, M.D., Ph.D., Raj K. Narayan, M.D., Roland Gerritsen van der Hoop, M.D., Ph.D., Thomas MacAllister, Ph.D., John D. Ward, M.D., Neta R. Nelson, M.P.H., and Nino Stocchetti, M.D. for the SYNAPSE Trial Investigators
Donald G. Stein, Ph.D.
Asa G. Candler Professor and Distinguished Professor
Department of Emergency Medicine
December 15 2014
Dr. Stein: I read with interest your interview with Dr. Brett Skolnick in which he discusses his NEJM publication  on the outcome of the progesterone trials. In full disclosure, I was not involved in either one of the clinical trials, but as a basic researcher, I have worked for decades in the field of traumatic brain injury (TBI) and have a long history examining progesterone as a potential neuroprotective agent.
The outcomes of the clinical trials were a huge disappointment to all of us working in the field. As you may already know, regardless of the drugs studied, the failure rate for TBI clinical trial outcomes is 100%. This is so sad, especially for patients and their families. With a 100% failure rate over almost 30 years of trial work, one has to ask, is preclinical research at fault because it does not replicate the conditions, trial designs and outcomes of clinical trials, or is there something fundamentally wrong with the way clinical trials are designed and conducted? Are the outcome measures really all that appropriate?
Dr. Skolnick’s strong defense of the Glasgow Outcome Scale as a primary outcome measure is puzzling. One of the key administrators of the clinical trial and the second author on Dr. Skolnick’s paper discusses the GOS in J. Clinical Investigation (2012), where Maas et al. address the question of how to evaluate “good” recovery versus “no recovery” or “bad” recovery:
Setting an arbitrary threshold which patients must cross to demonstrate clinical improvement is not reflective of the clinical situation and substantially reduces chances of showing benefit. Although perhaps intuitively attractive because it is so simple, the traditional approach to dichotomize the GOS is counterproductive and disregards potentially valuable information found in an ordinal scale. In the absence of early mechanistic endpoints, TBI investigators and regulatory authorities have adopted the GOS as the standard for primary efficacy analysis. 
Skolnick’s interview offers a strong defense of a short survey test that many neuropsychologists consider too simplistic and incomplete to evaluate the recovery of a brain-damaged patient. In addition to the insensitivity of the GOS to measure what critical functions recover over time, and questions about the validity of any self-reported survey, there may be social pressures affecting how patients and their caregivers respond to this brief (7-10 minute) questionnaire. At least in the US, a patient with serious brain injury who responds that s/he is doing well stands to lose his/her disability payments, among other benefits. How was this addressed in the final analysis and what could be the impact of this on reporting outcomes?
Besides the use of just a single, controversial outcome measure like the GOS, there are many other issues surrounding this large clinical trial that would have taken a much longer interview to discuss. The issues would include dose-duration and delay of treatment questions as well as other factors that can contribute so much variability to human clinical trial studies. There is little doubt that this clinical trial did not work, the question is: why? It is entirely possible that this clinical trial was fallible on a number of issues (see  for further discussion of this issue).
In the final analysis, given the serious problems with the outcome measures and design issues confronting such a large (and international) trial, I am not as convinced as Dr. Skolnick that progesterone simply does not work in all cases of TBI. He is completely right in stating that the trials as conducted are far from conclusive in showing progesterone benefit. That is a great pity, because these studies may never be tried again …even with better designs and outcome measures.
Before any further clinical work is done, I also think that our clinician colleagues have to address why they persist in using clinical trial outcome measures and designs that continue to produce a 100% failure rate in the translation of TBI drug interventions. Isn’t in time for a change? At the very least, some consideration ought to be given to alternative views on what the outcomes of the two current trials actually represent. In the interest of fairness, I hope you will give some consideration to discussing this in one of your future articles in Medical Research. I’d be willing to bet that there are a number of others who share my sentiments.
- Brett E. Skolnick, Ph.D., Andrew I. Maas, M.D., Ph.D., Raj K. Narayan, M.D., Roland Gerritsen van der Hoop, M.D., Ph.D., Thomas MacAllister, Ph.D., John D. Ward, M.D., Neta R. Nelson, M.P.H., and Nino Stocchetti, M.D. for the SYNAPSE Trial Investigators. A Clinical Trial of Progesterone for Severe Traumatic Brain Injury. NEJM December 10, 2014DOI: 10.1056/NEJMoa141109
- Roozenbeek B, Lingsma HF, Maas A, New considerations in design of clinical trials, Clinical Investigation, 2012.
- Shamy MCF, Stahnisch FW, Hill MD (2015) Fallibility: a new perspective on the ethics of clinical trial enrollment. Int J Stroke 10:2-6.