Arthur Kellermann - US grants

Traumatic brain injury (TBI) is a major cause of premature death and disability worldwide. Few effective treatments exist. Based on encouraging results from studies with animals, we hypothesize that early administration of progesterone to victims of moderate to severe TBI reduces secondary brain injury and improves neurological outcomes. Prior to proceeding with a full-scale clinical trial, we propose to conduct a pilot study by identifying and recruiting eligible subjects at a single level I trauma center. Consenting subjects will be randomly assigned to receive either IV infusion of progesterone or an equivalent volume of placebo. The study team, which will be blinded to treatment status, will monitor each subject's clinical progress and assess outcome at one month post-injury. The primary objectives of this pilot study are to: 1) achieve proper dosing of the study drug, 2) gather data on drug safety, and 3) generate preliminary evidence of efficacy. The secondary objective is to identify the most appropriate clinical subgroup(s) for subsequent treatment in a multi-center trial. To identify the correct dosage and infusion rate to achieve a steady state serum progesterone concentration (SSSPC) level of 450 nmole/L + 100 in our subjects, we will statistically examine the SSSPCs of the first ten subjects randomized to progesterone. To test the safety of the progesterone infusion, we will monitor patients for several unlikely, but potential complications of progesterone administration. To assess the potential efficacy of the progesterone for TBI, we will compare treatment groups with respect to duration of coma, death at one month post-injury, and most important, neurological outcome at one month post-injury. Three measures of neurological outcome will be used: the Glasgow Outcome Score, the Disability Rating Scale, and the Galveston Orientation and Amnesia Test. Once these objectives are accomplished, we will apply the lessons learned in this pilot study to mount a multi-center, randomized, double blind, placebo-controlled clinical trial of intravenous progesterone for treatment of traumatic brain injury. If the therapeutic benefits observed in animals are replicated in humans, administration of intravenous progesterone should produce several benefits, including: a) decreased duration of coma; b) decreased mortality; and c) improved neurological function. If these hypotheses are verified, this it will represent a major advance in the treatment of traumatic brain injury.

DESCRIPTION (provided by applicant): During the 1990s, 100,000 Americans died each year because of alcohol abuse or alcohol dependence (ANAD). Alcohol is the third leading preventable cause of mortality in the U.S. AA/AD burdens U.S. emergency departments (EDs). The estimated prevalence of ANAD in trauma centers ranges between 25- 50% of patient populations. Persons who are AA/AD take up half of all trauma beds and consume more than 15% of the national health care budget. Also, ANAD are associated with chronic disease, crime, losses in workplace productivity, and a spectrum of social costs. The goal of this project is to translate motivational interventions, successful in primary care settings to the ED environment by implementing screening and brief intervention (SBIRT) and referral to treatment to reduce at-risk drinking among ED patients. Specific Objectives: To participate as a local site for the NIH-NIAAA sponsored 'National Alcohol Screening Day' (NASD) focused, multi-center study designed to test the effectiveness of SBIRT as practiced by ED physicians, nurses, and physician assistants as part of clinical care in the ED setting to reduce levels of hazardous drinking among ED patients. To use the publicity and materials for NASD, and the training provided by the 'Boston University ED Alcohol Education Project' to increase adoption of SBIRT by ED practitioners. Hypotheses: 1. Among persons identified with ANAD in the ED setting, SBIRT counseling Nill result in significantly decreased frequency and quantity of self-reported alcohol use, reduced alcohol related health risk factors, and increased completion of aftercare referrals in the intervention group as measured at 3 and 6 month follow-up, as compared to a control group of persons identified with AA/AD in the ED setting who receive only written advice as measured at 3 and 6 month follow-up. 2. ED personnel who receive SBIRT training, and self-report as having positive experiences during the intervention period surrounding NSAD, will adopt or enhance their SBIRT of patients with ANAD in the ED setting.