Neurology/original research
ProTECT: A Randomized Clinical Trial of Progesterone for Acute Traumatic Brain Injury

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Study objective

Laboratory evidence indicates that progesterone has potent neuroprotective effects. We conducted a pilot clinical trial to assess the safety and potential benefit of administering progesterone to patients with acute traumatic brain injury.

Methods

This phase II, randomized, double-blind, placebo-controlled trial was conducted at an urban Level I trauma center. One hundred adult trauma patients who arrived within 11 hours of injury with a postresuscitation Glasgow Coma Scale score of 4 to 12 were enrolled with proxy consent. Subjects were randomized on a 4:1 basis to receive either intravenous progesterone or placebo. Blinded observers assessed patients daily for the occurrence of adverse events and signs of recovery. Neurologic outcome was assessed 30 days postinjury. The primary safety measures were differences in adverse event rates and 30-day mortality. The primary measure of benefit was the dichotomized Glasgow Outcome Scale–Extended 30 days postinjury.

Results

Seventy-seven patients received progesterone; 23 received placebo. The groups had similar demographic and clinical characteristics. Laboratory and physiologic characteristics were similar at enrollment and throughout treatment. No serious adverse events were attributed to progesterone. Adverse and serious adverse event rates were similar in both groups, except that patients randomized to progesterone had a lower 30-day mortality rate than controls (rate ratio 0.43; 95% confidence interval 0.18 to 0.99). Thirty days postinjury, the majority of severe traumatic brain injury survivors in both groups had relatively poor Glasgow Outcome Scale–Extended and Disability Rating Scale scores. However, moderate traumatic brain injury survivors who received progesterone were more likely to have a moderate to good outcome than those randomized to placebo.

Conclusion

In this small study, progesterone caused no discernible harm and showed possible signs of benefit.

Introduction

No pharmacologic agent has been shown to improve outcomes of traumatic brain injury.1 Methylprednisolone, once considered a mainstay of treatment, is harmful.2, 3, 4 A recent large-scale trial of magnesium was disappointing.5 Hypothermia produces variable effects and may be hazardous to brain-injured patients older than 45 years.6, 7, 8, 9

During the past decade, progesterone has emerged as a promising therapeutic candidate. Although progesterone’s nonneurologic effects are well known, the steroid also has neuroprotective properties.10 Progesterone is present in the brains of men and women in small but roughly equal concentrations. Progesterone receptors are widely distributed throughout the central nervous system. A growing body of animal studies indicates that administering progesterone shortly after traumatic brain injury reduces cerebral edema, prevents neuronal loss, and improves functional outcomes.10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35

Traumatic brain injury is a massive public health problem worldwide. Approximately 1.5 to 2 million Americans sustain a traumatic brain injury each year.36 In the United States, traumatic brain injuries annually cause 50,000 deaths, 235,000 hospitalizations, and 80,000 new cases of long-term disability.37, 38, 39, 40, 41, 42, 43, 44, 45 The Centers for Disease Control and Prevention (CDC) estimates that 5.3 million Americans are disabled from a previous traumatic brain injury.36 Aggregate lifetime costs exceed $56 billion per year.37

In light of promising preclinical evidence, we conducted a pilot clinical trial of intravenous progesterone to treat acute traumatic brain injury.

Section snippets

Study Design

Our study was a phase II, randomized, placebo-controlled clinical trial. Its primary objective was to assess the safety of administering progesterone to patients with moderate to severe acute traumatic brain injury. We also hoped to detect possible signs of benefit. Except for our lead statistician, everyone involved was blinded to treatment group assignment for the duration of the trial.

In the United States, intravenous progesterone has been authorized for experimental administration in only 3

Results

Two hundred eighty-one patients were screened between May 28, 2002, and September 17, 2004. Only 3 were missed. Common reasons for exclusion included GCS less than 4 or greater than 12 (17%), blood alcohol content 250 (13%), no next of kin (11%), unknown injury time (11%), unstable vital signs (9.2%), and unreliable GCS (9.2%). Six patients could not be enrolled because they presented during one of 3 study “holds.” One was excluded postconsent but before randomization because the treating team

Limitations

Our study was limited to adults. Brain injury is an enormous problem in pediatric age groups, but progesterone’s effects on brain-injured children are unknown. A separate trial will be needed to explore progesterone’s safety and effectiveness as a treatment for brain-injured children.

No discernible harms were noted in the 77 patients who were randomized to progesterone. However, small studies like ours are prone to type II error. Disproportionate allocation of subjects to the treatment group

Discussion

Progesterone offers a number of advantages over other experimental treatments for traumatic brain injury. Because it is lipid soluble, it rapidly crosses the blood-brain barrier and reaches equilibrium with the plasma within an hour of administration.66 It has a long history of safe use in men and women.47, 67, 68, 69, 70 The intravenous formulation we used can be easily administered by peripheral line.49 Because the agent is widely available in generic forms, it is inexpensive.

The mechanisms

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  • Cited by (0)

    Supervising editor: William G. Barsan, MD

    Author contributions: DWW, ALK, VSH, FCG, DWL, DDD, MMW, SWH, MF, and DGS conceived the study and designed the trial. DWW, ALK, VSH, PLC, MF, FCG, JPS, LLD, OAH, DSA, DWL, MMP, DDD, ABG, and SG participated in the clinical trial and obtained research funding. ALK, DWW, and PLC, supervised the conduct of the trial and data collection. DWW, ALK, DWL, DSA, PLC, and MMP undertook recruitment of patients and managed the data, including quality control. DDD provided the pharmacokinetic support for the study, including design and analyses. VSH and ABG provided statistical advice on study design and analyzed the data. DWW and ALK drafted the manuscript, and all authors contributed substantially to its revision. DWW takes responsibility for the paper as a whole.

    Funding and support: Supported by a grant from the National Institute for Neurological Disorders and Stroke, National Institutes of Health (1 R01 NS-39097-01A1 to AK) and the General Clinical Research Center at Emory University and Grady Memorial Hospital.

    Available online September 29, 2006.

    Reprints not available from the authors.

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