Traumatic Brain Injury (TBI) is a serious public health problem that affects about 1.5 million people per year in the US, with direct and indirect medical costs of over $50 billion. Rapid intervention to reduce the risk of death and disability is crucial. The diagnosis and treatment of TBI is an active area of preclinical and clinical research funded by NIH and other federal agencies.
But during the White House BRAIN Conference, a leading neurosurgeon painted a pessimistic picture of current treatments for acute TBI. In response to a question about clinical advances based on cellular neurobiology, Dr. Geoffry Manley noted that the field is on its 32nd or 33rd failed clinical trial. The termination of a very promising trial of progesterone for TBI had just been announced (the ProTECT III, Phase III Clinical Trial “based on 17 years of work with 200 positive papers in preclinical models”), although I couldn't find any notice at the time (Sept 30 2014).
Now, the results from ProTECT III have been published in the New England Journal of Medicine (Wright et al., 2014). 882 TBI patients from 49 trauma centers were enrolled in the study and randomized to receive progesterone, thought to be a neuroprotective agent, or placebo within 4 hours of major head injury. The severity of TBI fell in the moderate to severe range, as indicated by scores on the Glasgow Coma Scale (which rates the degree of impaired consciousness).
The primary outcome measure was the Extended Glasgow Outcome Scale (GOS-E) at six months post-injury. The trial was stopped at 882 patients (out of a planned 1140) because there was no way that progesterone would improve outcomes:
After the second interim analysis, the trial was stopped because of futility. For the primary hypothesis comparing progesterone with placebo, favorable outcomes occurred in 51.0% of patients assigned to progesterone and in 55.5% of those assigned to placebo.
Analysis of subgroups by race, ethnicity, and injury severity showed no differences between them, but there was a suggestive (albeit non-significant) sex difference.
Modified from Fig. 2 (Wright et al., 2014). Adjusted Relative Benefit in Predefined Subgroups. Note the red box p value for sex differences.
Squares to the left of the dotted line indicate that placebo performed better than progesterone in a given patient group, while values to the right favor progesterone. The error bars show confidence intervals, which indicate that nearly all groups overlap with 0 (representing zero benefit for progesterone) The red box indicates a near-significant difference between men and women, with women actually faring worse with progesterone than with placebo. You may quibble about conventional significance, but women on average deteriorated with treatment, while men were largely unaffected.
This was a highly disappointing outcome for a well-conducted study that built on promising results in smaller Phase II Clinical Trials (which were backed by a boatload of preclinical data). The authors reflect on this gloomy state of affairs:
The PROTECT III trial joins a growing list of negative or inconclusive trials in the arduous search for a treatment for TBI. To date, more than 30 clinical trials have investigated various compounds for the treatment of acute TBI, yet no treatment has succeeded at the confirmatory trial stage. Many reasons for the disappointing record of translating promising agents from the laboratory to the clinic have been postulated, including limited preclinical development work, poor drug penetration into the brain, delayed initiation of treatment, heterogeneity of injuries, variability in routine patient care across sites, and insensitive outcome measures.
If that isn't enough, a second failed trial of progesterone was published in the same issue of NEJM (Skolnick et al., 2014). This group reported on negative results from an even larger pharma-funded trial (SyNAPse, which is the tortured acronym for Study of a Neuroprotective Agent, Progesterone, in Severe Traumatic Brain Injury). The SyNAPse trial enrolled the projected number of 1180 patients across 21 countries, all with severe TBI. The percentage of patients with favorable outcomes at six months was 50.4% in the progesterone group and 50.5% in the placebo group.
The negative result of this study, combined with the results of the PROTECT III trial, should stimulate a rethinking of procedures for drug development and testing in TBI.
This led Dr. Lee H. Schwamm (2014) to expound on the flawed culture of research in an Editorial, invoking the feared god of false positive findings (Ioannidis, 2005) and his minions: small effect sizes, small n's, too few studies, flexibility of analysis, and bias. Schwamm pointed to problematic aspects of the Phase II Trials that preceded ProTECT III and SyNAPse, including modest effect sizes and better-than expected outcomes in the placebo group.
Hope for the Future
“And you have to give them hope.”
When the going gets tough in research, who better to rally the troops than your local university press office? The day after Dr. Manley's presentation at the BRAIN conference on Sept. 30, the University of California San Francisco issued this optimistic news release:
$17M DoD Award Aims to Improve Clinical Trials for Traumatic Brain Injury
An unprecedented, public-private partnership funded by the Department of Defense (DoD) is being launched to drive the development of better-run clinical trials and may lead to the first successful treatments for traumatic brain injury, a condition affecting not only athletes and members of the military, but also millions among the general public, ranging from youngsters to elders.
Under the partnership, officially launched Oct. 1 with a $17 million, five-year award from the DoD, the research team, representing many universities, the Food and Drug Administration (FDA), companies and philanthropies, will examine data from thousands of patients in order to identify effective measures of brain injury and recovery, using biomarkers from blood, new imaging equipment and software, and other tools.
. . .
“TBI is really a multifaceted condition, not a single event,” said UCSF neurosurgeon Geoffrey T. Manley, MD, PhD, principal investigator for the new award... “TBI lags 40 to 50 years behind heart disease and cancer in terms of progress and understanding of the actual disease process and its potential aftermath. More than 30 clinical trials of potential TBI treatments have failed, and not a single drug has been approved.”
The TED (TBI Endpoints Development) Award is meant to accelerate research to improve TBI diagnostics, classification, and patient selection for clinical trials. Quite a reversal of fortune in one day.
Out of the ashes of two failed clinical trials, a phoenix arises. Hope for TBI patients and their families takes wing.
Further Reading (and viewing)
White House BRAIN Conference (blog post)
90 min video of the conference
Brief Storify (summary of the conference)
ClinicalTrials.gov listings for SyNAPSe and ProTECT III.
Schwamm, L. (2014). Progesterone for Traumatic Brain Injury — Resisting the Sirens' Song New England Journal of Medicine, 371 (26), 2522-2523 DOI: 10.1056/NEJMe1412951
Skolnick, B., Maas, A., Narayan, R., van der Hoop, R., MacAllister, T., Ward, J., Nelson, N., & Stocchetti, N. (2014). A Clinical Trial of Progesterone for Severe Traumatic Brain Injury New England Journal of Medicine, 371 (26), 2467-2476 DOI: 10.1056/NEJMoa1411090
Wright, D., Yeatts, S., Silbergleit, R., Palesch, Y., Hertzberg, V., Frankel, M., Goldstein, F., Caveney, A., Howlett-Smith, H., Bengelink, E., Manley, G., Merck, L., Janis, L., & Barsan, W. (2014). Very Early Administration of Progesterone for Acute Traumatic Brain Injury. New England Journal of Medicine, 371 (26), 2457-2466 DOI: 10.1056/NEJMoa1404304
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