Study Design

The Progesterone for Traumatic Brain Injury, Experimental Clinical Treatment (PROTECT III) trial was a phase 3, randomized, double-blind, placebo-controlled clinical trial designed to determine the efficacy of early intravenous administration of progesterone versus placebo for treating patients with acute nonpenetrating TBI caused by a blunt mechanism. The trial was funded by the National Institute of Neurological Disorders and Stroke (NINDS) and was conducted through the NINDS-funded Neurological Emergencies Treatment Trials (NETT) network. The NETT network is organized into 22 academic medical centers that operate as clinical hubs, each of which has one or more study sites. The investigators were responsible for all the elements of the trial, including the design, data collection, analysis, and interpretation. All the authors wrote the manuscript and vouch for the data and analysis. The trial was conducted under Investigational New Drug application 104,188 with the Food and Drug Administration (FDA). The study was conducted in accordance with the protocol, available with the full text of this article at NEJM.org.

The PROTECT III trial was conducted at 49 trauma centers in the United States. Rigorous training and certification of the investigators, coordinators, and outcomes assessors were performed initially and updated throughout the study. In addition to strict compliance with the study protocol, critical elements of TBI management were standardized across the study sites to minimize the effects of practice variability and secular trends. Adherence to both the study protocol and the TBI management guidelines of the trial were centrally monitored daily. Failures of adherence to the study protocol were identified as protocol deviations, and failures of adherence to standardized care guidelines were defined as clinical transgressions. Both required a prompt response and corrective action.

The trial met the exception from informed-consent requirements for emergency research under FDA code of regulations 21 CFR 50.24.7 As specified by the federal regulations, the institutional review board at each site reviewed and approved local community consultation and public disclosure activities. When a legally authorized representative was available, written informed consent was obtained before enrollment of the patient. For patients enrolled under the exemption from informed consent, patients or their legally authorized representatives were notified about enrollment by the study team as soon as possible and were asked to provide written informed consent to continue in the study. Safety oversight was provided by an NINDS-appointed data and safety monitoring board and two independent medical safety monitors.

Study Patients

Eligible patients were adults who had severe, moderate-to-severe, or moderate TBI due to a blunt mechanism, with a Glasgow Coma Scale8 (GCS) score of 4 to 12 (on a scale of 3 to 15, with lower scores indicating a lower level of consciousness). Patients were enrolled if the study treatment could be initiated within 4 hours after injury.

Patients were excluded if, before enrollment, the treatment team determined clinically that the injury sustained was nonsurvivable; the patient had bilateral dilated, unresponsive pupils; cardiopulmonary resuscitation was performed; or the patient had physiological findings of hypoxemia, hypotension, spinal cord injury, or status epilepticus. Additional exclusion criteria were pregnancy, status as a prisoner or ward of the state, severe intoxication (ethanol level, >249 mg per deciliter), and a known history of reproductive cancer, allergy to progesterone or a fat-emulsion vehicle, or a blood-clotting disorder. Patients with active myocardial infarction, ischemic stroke, pulmonary embolism, or deep-vein thrombosis were also excluded. In addition, patients were excluded if they were wearing an opt-out bracelet or were listed in a registry of persons preemptively requesting not to participate in this trial.

Study Intervention

Immediately after enrollment, patients were randomly assigned to receive an infusion containing either progesterone or placebo. Randomization was performed with the use of a combination of minimization and biased-coin algorithms to avoid imbalances in initial injury severity, sex, age, or enrollment site.

Study-drug kits containing four vials of progesterone in ethanol (active treatment) or ethanol alone (placebo) were prepared by the Emory Investigational Drug Service. Drug kits and their contents were identical in appearance, and study assignments remained concealed from all site pharmacists and study teams. Site pharmacists prepared the coded kit assigned by the randomization algorithm by mixing a weight-based dose (0.05 mg of progesterone per kilogram of body weight per milliliter of infusate) from the provided vials and a 250-ml bag of fat-emulsion vehicle (Intralipid 20%, Fresenius Kabi) every 24 hours. The study treatment was initiated within 4 hours after injury and consisted of a 1-hour loading dose, 71 hours of maintenance infusion, and a 24-hour infusion taper. The study drug was infused continuously through a dedicated intravenous catheter at a dose of 14.3 ml per hour for 1 hour and then at 10 ml per hour for 71 hours; the dose was then tapered by 2.5 ml per hour every 8 hours, for a total treatment duration of 96 hours.

Local study teams followed the patients closely. Data on serious adverse events were collected throughout the duration of the study (6 months), and data on all adverse events were collected during the first week. Data on clinical transgressions were collected and reported daily during hospitalization.

Study Outcomes

The primary outcome was functional recovery as determined with the use of the Extended Glasgow Outcome Scale9,10 (GOS-E) at 6 months (±30 days) after randomization. A GOS-E score of 1 indicates death, 2 indicates a vegetative state, 3 or 4 indicates severe disability, 5 or 6 indicates moderate disability, and 7 or 8 indicates good recovery. Consistent scoring was ensured by means of rigorous training and quality assessment.

A favorable outcome was defined with the use of a stratified dichotomy of the GOS-E scores in which the definition of favorable depended on the severity of the initial injury. The index GCS score, the highest reliable GCS score documented before randomization, determined the initial injury severity. (If the patient was intubated, the index GCS motor score was used to assess severity; scores on the motor component of the GCS range from 1 to 6, with lower scores indicating a lower level of consciousness.) Patients with a less severe initial injury had to have a better recovery than those with a more severe injury in order to have a favorable outcome. Patients with a severe initial injury (an index GCS score of 4 to 5 or, if the patient was intubated, an index GCS motor score of 2 to 3) were considered to have a favorable outcome if the 6-month GOS-E score was 3 or higher. Patients with a moderate-to-severe initial injury (an index GCS score of 6 to 8 or, if the patient was intubated, an index GCS motor score of 4 to 5) were considered to have a favorable outcome if the 6-month GOS-E score was 5 or higher, and those with a moderate initial injury (an index GCS score of 9 to 12) were considered to have a favorable outcome if the 6-month GOS-E score was 7 or higher.

Secondary outcome measures included mortality, the Disability Rating Scale score,11 the rates of nine prespecified adverse events that were considered to be potentially associated with treatment, and the rates of all reported adverse events and serious adverse events. Data on cognitive, psychological, and neurologic outcomes were also collected but are not reported here.

Statistical Analysis

The primary objective was to determine whether progesterone was associated with an absolute increase of 10 percentage points, as compared with placebo, in the proportion of patients with a favorable outcome. We estimated that a total sample of 1140 patients was required in order for the study to detect that effect with 85% power, assuming that 50% of the patients in the placebo group would have a favorable outcome and assuming a two-sided type I error probability of 0.05. This calculation included inflation for a 10% nonadherence rate (owing to withdrawal of consent, loss to follow-up, or treatment crossover) and two equally spaced interim analyses for efficacy and futility with the use of O'Brien and Fleming stopping boundaries.12

After randomization, patients were included in the primary analysis under the intention-to-treat principle. The primary efficacy hypothesis was tested with the use of a generalized linear model relating the probability of a favorable outcome to the study treatment, with adjustment for index GCS score strata, sex, and age. Standard multiple-imputation methods13 were used to impute outcomes for patients without the primary outcome or with the primary outcome obtained outside the specified time window. A complete case sensitivity analysis was also performed. Prespecified covariates were evaluated for an interaction effect with the study treatment. Subgroup analyses were performed for sex, race, ethnic group, and index GCS score strata, regardless of interaction effect. Other subgroups were considered only if the interaction was statistically significant (alpha level of 0.20), was clinically significant, and involved a sufficiently large sample (>100 patients).