JC: Progesterone’s pleiotropic failure in head injury. St.Emlyn’s

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Pleiotropic might just be my favourite new word, thus overtaking November’s great word ‘Glyptotek’ (Danish for Sculpture museum). I digress. Pleiotropic is a word used to describe the ability of a gene to affect multiple phenotypic traits. Great, what’s that got to do with traumatic brain injury you ask? Well, Progesterone has been described as having pleiotropic properties as an ‘all in one, drug cocktail, developed by Mother Nature, By God for this purpose’ (to treat brain injury).

Now that’s not really me talking, it’s David Wright from the Emory University of Medicine as you can hear in the short link below.

Progesterone has been touted as a potential treatment for brain injury for many years and there is a nice review on the rationale and potential for its use HERE as an open access paper from the NATURE group. In animal studies progesterone has showed some considerable promise as a neuroprotective agent following stroke, spinal cord injury and traumatic brain injury. The effects include less neuronal loss, less cerebral oedema and an improvement in functional recovery.

I attended a lecture a couple of years back from an American chap detailing the science behind the use of hormones in brain injury and it was pretty impressive, though not definitive. They rightly pointed out that we needed large human trials to tell us whether we can translate theory and lab work into the real world. Early phase two trials by Xiao (159 patients) and Wright (77 patients) have also shown promise with potential benefits to patients.

The first large RCT in humans appeared recently in the NEJM and it’s worth a read. It’s open access at the moment so there is no excuse this week. Read the full paper.

Screenshot 2014-12-29 17.22.16

What type of study is this?

It’s an RCT which is exactly what we want to see. An RCT should reduce the potential for bias and randomly allocate therapy to patients. Patients were allocated to early administration of 0.05mg/Kg of progesterone over 72 hours split between a one hour loading dose then 71 hours of infusion. Patients were randomised using a technique called minimisation which selects the treatment for a patient based on which will balance the groups for later analysis against known confounders. It’s really rather clever and is my second favourite method after Latin Squares (Ed – you’re not well).

Who was studied

Patients with a potentially survivable (in the opinion of the clinicians) head injury and a GCS of 4-12 were eligible if treatment could be started within 4 hours of injury. The study did not enrol patients with penetrating injury and there were a number of other typical exclusions, but in general I think these are patients similar to the ones I see in the UK.

The trial aimed to recruit 1140 patients with an aim to demonstrate a 10% improvement in patients with a favourable outcome on the Extended Glasgow Outcome Score. That’s quite a large difference in my opinion and would represent an NNT of 10, which apart from surgery is probably a higher NNT than anything else we do for head injured patients (please correct me if I’m wrong). It’s also way above the NNT for aspirin in MI, or TXA in traumatic bleeding. The point is that even at 1140 patients this trial was seeking a fairly large treatment effect.

The trial was stopped early as a result of ‘futility’ as after an interim analysis of 882 patients it became apparent that the 10% improvement was unlikely yo be achieved. Interim analyses can be dangerous, but if planned against predetermined recruitment targets they can be very helpful. In this case the interim analysis was planned and so we can be happy with the process.

What did they find?

Amongst the 882 patient recruited the authors found no significant benefit to progesterone over placebo. In terms of favourable outcome the findings were not in favour of progesterone (relative benefit 0.95 CI 0.85-1.06).  Sub group analyses based on injury severity, sex, ethnicity, race or isolated head injury also failed to reveal a group that appeared to do better with progesterone.

So what?

This trial is well designed, of a reasonable size and appears to have been well conducted. It look like curtains for progesterone, but that really does ask the question why this and so many other therapies for TBI have failed when tested in RCTs (anyone ever given steroids for head injury?).

Whether Progesterone is pleiotropic, earthly, or divine I don’t know, but it seems unlikely to have a role in TBI treatment for my patients.

You should also read the editorial on the trial which highlights other concerns regarding translation research in brain injury.




Further reading

LITFL R&R 21 http://lifeinthefastlane.com/rr-in-the-fastlane-021/

Progesterone for Acute Brain Injury: Cochrane Collaboration.

Xiao G, Wei J, Yan W, Wang W, Lu Z. Improved outcomes from the administration of progesterone for patients with acute severe traumatic brain injury: a randomized controlled trial. Crit Care 2008; 12: R61.

Wright DW, Kellermann AL, Hertzberg VS, Clark PL, Frankel M, Goldstein FC, et al. ProTECT: a randomized clinical trial of progesterone for acute traumatic brain injury. Ann Emerg Med 2007; 49: 391–402.

The neuroprotective effects of progesterone on traumatic brain injury: current status and future prospects Acta Pharmacologica Sinica (2013) 34: 1485–1490; doi: 10.1038/aps.2013.160; published online 18 Nov 2013. Jing Wei1 and Guo-min Xiao2

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