Neta R. Nelson (corresponding author), Roland Gerritsen van der Hoop, and Thomas W. MacAllister , BHR Pharma, LLC
Known primarily as a reproductive hormone, progesterone is increasingly recognized as a so-called “neurosteroid.” Neurosteroids are normally produced in the central nervous system (CNS) and they act locally in the CNS. In fact, progesterone is produced in the CNS in response to traumatic injury [2, 3, 8]. The hypothesis that this endogenous neurosteroid has therapeutic potential in traumatic injuries to the CNS is supported by over 180 preclinical studies from more than two dozen laboratories, in four species and 22 different brain injury models , and three Phase 2 clinical studies in traumatic brain injury (TBI). Based on promising results from Phase 2 studies of progesterone in TBI in the US and China, BHR Pharma, LLC is conducting SyNAPSe, an international multi-center Phase 3 clinical trial to demonstrate the efficacy and safety of BHR-100 progesterone lipid infusion, in severe TBI patients. Enrollment is past the half-way mark, remains ongoing, and the results of a planned interim analysis are expected in early 2013.
TBI is a major cause of death and disability worldwide. Severe TBI impacts not only the life of an individual and the family, but it also has a large societal and economic toll. Survivors often face a long-term or lifelong need for assistance in performing activities of daily living due to physiological, cognitive, and emotional challenges. Numerous clinical trials in moderate-to-severe TBI during the past 30 years, with over 25 medicinal agents, have failed to demonstrate sufficient efficacy in clinical outcomes in the overall study population [1,4,5], and none has received regulatory approval. Most of these drugs are presumed to exert their activity through a single mechanism of action; they have targeted inflammation (e.g. corticosteroids and bradykinin inhibitors), glutamate excitotoxicity (selfotel and traxoprodil), lipid peroxidation (tirilazad) and calcium cellular influx (nimodipine). Some agents have more than one presumed mechanism of action, such as magnesium sulfate and cannabinoids. In comparison, progesterone’s promise in TBI may be due largely to its pleiotropic properties, meaning that progesterone can operate on a number of different pathways simultaneously .
Although historically known as a gonadal hormone involved in the menstrual cycle, pregnancy, and embryogenesis, progesterone is an important centrally acting agent and is synthesized by glial cells and neurons in the brains of males and females. Glial cells in particular are involved in both synthesis and metabolism of progesterone in both normal and injured brains . In a study carefully characterizing serum hormone profiles following severe TBI , elevated progesterone levels were seen immediately post-injury, and then rapidly declined. Preclinical studies also show increased levels of progesterone following stroke induction, with an acute but transient protective effect . These observations on endogenous progesterone support the notion of exogenous administration of this sex hormone for neuroprotection in several types of brain injury.
Mechanistic and Preclinical Plausibility
Numerous studies in various species have demonstrated that progesterone has neuroprotective effects in TBI as well as stroke, such as reduced post-injury edema and improved cognitive recovery from secondary neuronal loss caused by contusion injury, through multiple mechanisms. Recently the importance of progesterone and its receptors was demonstrated in knock-out mice in a cerebral ischemia model, where the neuroprotective effect of endogenous and exogenous progesterone could be seen only in animals with intact progesterone receptors . Potential mechanisms of action include:
- Reducing vasogenic edema and cytotoxic edema
- Preventing inflammation in part by modulating cytokine production and action
- Reducing free radical damage
- Decreasing excitotoxicity by upregulating neurotransmitter GABA-A
- Reducing neuronal apoptosis [2,6]
Progesterone has the largest body of preclinical evidence of any medicinal agent previously studied in TBI [6,7]. Perhaps an ideal drug candidate for TBI, progesterone readily crosses the blood-brain barrier and has a long history of safe use in a variety of conditions.
In a pilot and two Phase 2 studies conducted in moderate-to-severe TBI patients [9,10,11], progesterone showed promising efficacy results in mortality and overall functional outcomes without meaningful safety signals. In both Phase 2 studies, mortality in the active group was approximately half that in the placebo group, and one study reached statistical significance on the dichotomized Glasgow Outcome Scale (GOS) at 3 and 6 months. BHR Pharma, LLC is conducting SyNAPSe, an international multi-center double-blind placebo-controlled Phase 3 clinical trial to demonstrate the efficacy and safety of BHR-100, progesterone lipid infusion, in 1180 severe TBI patients (Glasgow Coma Scale 3-8).
The aim of the study is to determine superiority of BHR-100 i.v. progesterone infusion compared to placebo infusion, on the GOS in patients with severe TBI at 6 months post injury. In addition, the safety and clinical benefits of BHR-100 treatment will be assessed on adverse events, mortality, GOS-Extended, the quality of life SF-36 questionnaire, and other secondary measures.
BHR-100 active drug product is a ready-to-use, sterile intravenous emulsion formulation containing soybean oil and progesterone. The placebo drug product is the same preparation as BHR-100, without progesterone. Subjects are treated with a loading dose of 0.71 mg/kg/hr of BHR-100 or placebo for the first hour followed by a continuous maintenance infusion of 0.5 mg/kg/hr, for a total of 120 hrs/5 days. The infusion must be initiated within 8 hrs of the brain injury.
Approximately 150 trial sites are participating in the U.S., Argentina, Europe, and Asia. Sites are Level 1 Trauma Centers or equivalent. Country selection depends on potential numbers of patients with severe TBI, quality standards of care for TBI, and the regulatory environment. Site selection further depends on the potential patient case load, investigator experience in conducting clinical trials in TBI or other acute indications, and existing infrastructure and departmental collaboration to succeed in this trial. In addition, these centers must follow standards of care for TBI patients based on Brain Trauma Foundation, American Brain Injury Consortium (ABIC), or European Brain Injury Consortium (EBIC) guidelines.
Subjects are randomized in a 1:1 ratio to treatment with BHR-100 or placebo. Randomization is conducted centrally and stratified by region. Study treatment must begin within 8 hours after the injury and is administered as a continuous i.v. infusion over 5 days. All study subjects receive the standard of care for TBI at the participating institution, regardless of the investigational treatment assignment. The primary outcome (GOS) is assessed at 6 months post-injury. Secondary endpoints include the GOS-E, mortality, and the SF-36. An interim analysis is planned once 400 subjects (200 per treatment arm) complete the 6-month assessment. The study design was developed in collaboration with BHR Pharma’s Steering Committee, ABIC, and EBIC. CT scans at baseline and Day 6 post-injury are centrally reviewed to confirm eligibility (post-hoc) and for secondary endpoint analysis. ABIC conducts central review of the GOS and GOS-E on all subjects and additionally conducts reviews on a subset of subjects for compliance with prescribed treatment guidelines. A Data Safety Monitoring Board is responsible for overseeing the trial and periodically reviews safety and efficacy data, including the interim analysis.
As patients in this study are not able to provide informed consent due to their baseline clinical status (GCS 3-8), proxy consent is obtained from a Legally Authorized/ Legally Accepted Representative per local country regulations and IRB/EC requirements. Consent must be obtained in time to start the study drug infusion within 8 hours of the TBI.
Key Inclusion Criteria:
- Age between 16 and 70 years, inclusive (or as required by local regulations)
- Weight from 45 to 135 kg, inclusive
- Closed (non-penetrating) head trauma no more than 8 hours before initiation of study drug infusion (exposed dura mater is acceptable in case of depressed skull fractures)
- TBI diagnosed by history and clinical examination
- GCS total score between 3 to 8, inclusive
- At least one reactive pupil
- Evidence of TBI confirmed by abnormalities consistent with trauma on CT scan upon admission (Marshall’s CT classification >I)
- Indication for ICP monitoring
Key Exclusion Criteria:
- Estimated life expectancy < 24 hours as determined by the Investigator
- Prolonged and/or uncorrectable hypoxia or hypotension at the time of randomization
- Any spinal cord injury
- Penetrating head injury (see Inclusion 3)
- Coma suspected primarily due to other causes (e.g. alcohol)
- Pure epidural hematoma
The evaluation of some criteria is left to the investigator's best judgment at the time of randomization; for example, sites are advised to evaluate ‘estimated life expectancy < 24 hours’ against their intention to treat the patient, regardless of study enrollment. If the treating physicians determine that a patient is so severely injured that no further care will be given and the patient will be permitted to die, then such a patient should not be enrolled into this trial. However, if they intend to make all efforts to save the patient's life in the expectation that there is a chance for the patient to survive, then that patient is suitable for enrollment, as far as this particular exclusion criterion is concerned.
Similar guidance is applied to defining ‘penetrating head injury’. Injuries in which the bone as well as the dura mater have been penetrated, including bone fragments penetrating into the brain, and deeply depressed skull fractures would be excluded. A patient undergoing surgery (e.g. decompressive craniectomy, evacuation of hematoma) before randomization would not be excluded; neither would patients with small amount of subdural air due to skull base fracture. Inclusion of penetrating skull injury without dural penetration or parenchyma penetration would depend on the amount of CT demonstrated damage. A patient with this type of skull injury AND a Marshall score of 2 or more (and meets all the other criteria) would be eligible for the trial.
Overall, Regulatory, and Site Status
The U.S. Food and Drug Administration has indicated that, if successful, SyNAPSe may be sufficient to support the new drug approval of BHR-100, compared to the usual requirement for two Phase 3 trials. However, a number of factors would need to be taken into consideration, such as statistical significance and effect size and consistency. BHR Pharma received Fast Track status from the FDA in March 2010 and Special Protocol Approval in June 2010. BHR also has obtained FDA’s Orphan Drug Designation based on the less-than-200,000 patient annual incidence of severe/moderate TBI. The study has received regulatory approval in 21 countries, beginning in the U.S. and most recently in Malaysia. At the time of this writing, approximately 150 sites are participating in 20 countries. There have been two DSMB reviews with no significant findings noted, and permission was granted to continue the trial. Results of the Interim Analysis on 400 six-month outcomes are expected at the end of this year. The study is conducted under U.S. IND number 104,330 and EudraCT Number 2010-018283-16.
Most participating sites have enrolled patients (range = 1-27 patients/site). Enrollment has passed the halfway mark (currently at 635 of 1180 patients). The distribution of baseline GCS at randomization is variable, with 7 being the most common (Figure 1). Gender distribution is typical for TBI trials (78% are male). Age ranges from 17-70 years, with a mean of 37 and a median of 34, showing a predominance of patients younger than 40. The causes of the TBI include auto (34%) and motorcycle (22%) accidents, falls (19%) and pedestrian traffic accidents (9%).
Figure 1: Distribution of SyNAPSe Trial Subjects by Baseline (Entry) GCS
Patients enter the study every day of the week, although slightly more often on the weekend, and at all hours of the day and night. The peak times of randomization are evening and late night hours. These parameters are indicative of the 24 hrs/7 days/week requirements of staff availability at participating centers to evaluate a potential patient, and complete the consent, screening, and randomization process.
The SyNAPSe global, multi-center trial of progesterone in severe TBI may, within a year or so, provide the basis for the first approved neuroprotective agent to treat severe TBI. BHR-100 is a shelf-stable, ready-to-use formulation that is a potentially life-saving medication for severe TBI patients. The current program builds on the most extensive body of combined preclinical and clinical evidence for any medicinal agent studied in TBI clinical trials to date. If successful, this trial will provide to patients with TBI, and their families, significant hope for better outcomes.
Endorsed by ABIC (American Brain Injury Consortium) and by EBIC (European Brain Injury Consortium).
BHR Pharma acknowledges the invaluable assistance provided by its Steering Committee, ABIC, and EBIC. INC Research and PRA International are the Contract Research Organizations managing the trial for BHR Pharma.
ClinicalTrials.gov Identifier: NCT01143064
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