Abstract
Despite hundreds of positive preclinical studies and two successful Phase II clinical trials, two large Phase III trials of progesterone treatment for traumatic brain injury were recently ended with no finding of any difference between the test drug and placebo. This chapter discusses some possible reasons for this outcome and proposes returning to Phase II and using a more effective clinical trial design. Specifically, we propose dose and duration of treatment optimization following allometric scaling principles to convert rat mg/kg/day dose to the appropriate human dose. We also propose to verify that the vehicle, at the concentration needed for patients, does not have antiinflammatory or neuroprotective clinical effects. Finally, preclinical animal studies should be conducted to determine whether the lipid vehicles used might alter the drug effects at the required concentrations.
Keywords
Allometric scaling, Progesterone, ProTECT III, SyNAPSe, Traumatic brain injury
Acknowledgments
With thanks to Leslie McCann for her unflagging patience in the editing of the manuscript. And with great appreciation for all of those laboratory scientists who have dedicated so much effort to finding a safe and effective treatment for TBI.
Disclosure
This paper discusses some concepts presented in other papers by the authors. Although DGS, IS, and Emory University hold patents on the use of progesterone for several medical indications, no royalties, income, or licensing fees are currently being generated by this intellectual property. RBH has no financial or other potential conflicts regarding this work.
Introduction: Progesterone Treatment Showed Promise in Preclinical Research
Although in many animal models of CNS injury, acute-stage treatment with progesterone demonstrated multifactorial benefits in the repair of the damaged brain, the Phase III translation to effective clinical outcome was disappointing. Over 300 preclinical studies listed on PubMed in both male and female subjects demonstrate that, given within the first few days after a traumatic brain injury (TBI), progesterone can modulate the expression of inflammatory cytokines, reduce levels of glutamate toxicity, attenuate both vasogenic and intracellular cerebral edema, prevent apoptosis and necrosis, restore the functions of the blood–brain barrier, and improve functional outcomes on sensory, cognitive, and motor behaviors. At the cellular level, giving progesterone early in the injury cascade can stimulate glial cells to increase myelin formation and restore metabolic function through its effects on the mitochondrial transition pore, and modify calcium channel activity to stabilize cellular metabolism, reducing the cytochemical cascade that can lead to further cell death in the days, weeks, and months after injury.
Progesterone is also known to have growth-promoting properties in the central nervous system. In preclinical experiments, it stimulates the expression and release of neurotrophic factors such as brain-derived neurotrophic factor, nerve growth factor, and insulin-like growth factor, which repair the damaged brain by stimulating neurogenesis, protecting against axonal degeneration, and enhancing synaptogenesis. Many genes involved in the expression of trophic factors and the inhibition of inflammatory cytokines can be regulated by progesterone, because it works through multiple receptor mechanisms throughout the brain. In laboratory experiments, progesterone and its metabolites consistently produce these beneficial effects in the brain and spinal cord after traumatic contusion injuries, nerve crush injuries, diffuse axonal injury, stroke, hemorrhage, cytotoxic injury, and even in degenerative neuropathologies. For a more detailed understanding of how progesterone and its metabolites modulate the cascade of mechanisms leading to both neuronal loss and repair over the course of brain insult, see , and .
Despite a few reports in the preclinical literature showing no benefits of progesterone treatment ( ), with no known toxic effects and so much experimental data supporting its neuroprotective properties, why did this well-known and well-established drug show no translational promise in Phase III clinical trials?
Introduction: Progesterone Treatment Showed Promise in Preclinical Research
Although in many animal models of CNS injury, acute-stage treatment with progesterone demonstrated multifactorial benefits in the repair of the damaged brain, the Phase III translation to effective clinical outcome was disappointing. Over 300 preclinical studies listed on PubMed in both male and female subjects demonstrate that, given within the first few days after a traumatic brain injury (TBI), progesterone can modulate the expression of inflammatory cytokines, reduce levels of glutamate toxicity, attenuate both vasogenic and intracellular cerebral edema, prevent apoptosis and necrosis, restore the functions of the blood–brain barrier, and improve functional outcomes on sensory, cognitive, and motor behaviors. At the cellular level, giving progesterone early in the injury cascade can stimulate glial cells to increase myelin formation and restore metabolic function through its effects on the mitochondrial transition pore, and modify calcium channel activity to stabilize cellular metabolism, reducing the cytochemical cascade that can lead to further cell death in the days, weeks, and months after injury.
Progesterone is also known to have growth-promoting properties in the central nervous system. In preclinical experiments, it stimulates the expression and release of neurotrophic factors such as brain-derived neurotrophic factor, nerve growth factor, and insulin-like growth factor, which repair the damaged brain by stimulating neurogenesis, protecting against axonal degeneration, and enhancing synaptogenesis. Many genes involved in the expression of trophic factors and the inhibition of inflammatory cytokines can be regulated by progesterone, because it works through multiple receptor mechanisms throughout the brain. In laboratory experiments, progesterone and its metabolites consistently produce these beneficial effects in the brain and spinal cord after traumatic contusion injuries, nerve crush injuries, diffuse axonal injury, stroke, hemorrhage, cytotoxic injury, and even in degenerative neuropathologies. For a more detailed understanding of how progesterone and its metabolites modulate the cascade of mechanisms leading to both neuronal loss and repair over the course of brain insult, see , and .
Despite a few reports in the preclinical literature showing no benefits of progesterone treatment ( ), with no known toxic effects and so much experimental data supporting its neuroprotective properties, why did this well-known and well-established drug show no translational promise in Phase III clinical trials?
The Phase II Trials
About 10 years ago, two small, single-center clinical trials began to test progesterone in patients with moderate to severe TBI. ProTECT II ( ) was a randomized, double-blind, placebo-controlled trial that enrolled consenting adult patients of both sexes within 11 h after their injuries with moderate-to-severe Glasgow Coma Scores (GCS) of 4–12 (detail in Table 1.1 ). A lower GCS score indicates a lower level of consciousness; the best score, 15, represents the best possible outcome.
| ProTECT II a | Xiao et al. b | |
|---|---|---|
| Centers | Grady Hospital, Atlanta, GA, USA | Clinical Medical College of Hangzhou, China |
| Patients screened | 281 | 230 |
| Final enrollment | 100 | 159 |
| Percent male | 71 | 72 |
| Waiver of consent | No | No |
| Admission criteria: Diagnosis | GCS 4–12 | GCS 3–8 |
| Admission criteria: Age range | ≥18 | 18–65 |
| Mean patient age | 36 | Progesterone: 30 Placebo: 31 |
| Time to start of treatment | ≤11 h | ≤8 h |
| Study Design | ||
| Double-blind | ✓ | ✓ |
| Randomization | 4:1 | 1:1 |
| Primary outcome measures | Frequency of SAEs Mortality at 30 days | GOS dichotomized |
| Secondary outcome measures | 30-day GOS-E dichotomized 30-day DRS | FIM Mortality at 3 and 6 months |
| Protocols | ||
| Vehicle/placebo | Intralipid | Camellia oil |
| Route of administration | i.v. | i.m. |
| Test drug administration | Total: 3 days at 12 mg/kg/day: Loading dose 0.71 mg/kg/h at 14 mL/h for 1 h, then 10 mL/h of 0.5 mg/kg/h for 11 h, then 5 doses at 10 mL/h to deliver 0.5 mg/kg/h for 11 h | Total: 5 days 1 mg/kg, then once every 12 h for 5 days at 2 mg/kg/day A single-dose volume of 0.05 mL/kg over 5 consecutive days |
| Findings | ||
| Mortality/morbidity | 30 days Severe progesterone 13.2% Severe placebo 40.0% Moderate progesterone 16.7% Moderate placebo 14.3% | 6 months Progesterone 18% Placebo 32% |
| Functional recovery | GOS at 30 days Severe progesterone 21.2% Severe placebo 26.7% Moderate progesterone 55.6% Moderate placebo 0% DRS mean total at 30 days Severe progesterone 10.7 Severe placebo 4.4 Moderate progesterone 5.0 Moderate placebo 12.7 | GOS score at 3 months Progesterone 47% Placebo 31% GOS score at 6 months Progesterone 58% Placebo 42% FIM score at 3 months PROG 8.02 ± 1.73 Placebo 7.35 ± 1.89 FIM score at 6 months PROG 9.87 ± 1.17 Placebo 8.95 ± 1.05 |
| SAEs due to treatment | 0 | 0 |
Patients received standard of practice care plus or minus progesterone treatment by continuous i.v. infusion at 12 mg/kg/day for 3 days in Intralipid vehicle. The frequency of serious adverse events (SAEs) and mortality at 30 days postinjury were the measures of drug safety. The primary measure of functional benefit, also measured only at 30 days post-TBI, was the dichotomized Glasgow Outcome Scale-extended (GOS-E). The Disability Rating Scale (DRS), another quality of life rating-scale measure, was also used. No SAEs were attributable to the progesterone treatment. At 30 days after injury, the progesterone-treated patients with severe TBI (GCS 4–8) remained in coma longer but had a significantly lower mortality compared to patients given only Intralipid. However, upon emerging from their comas, these same patients had somewhat worse GOS-E and DRS scores compared to controls. The investigators speculated that the drug may have increased the incidence of survival in a badly injured treated subpopulation who probably would have died if they had been in the control group. In contrast, the moderately injured (GCS 9–12) TBI patients given progesterone had significantly better 30-day outcomes on the GOS-E and DRS than the placebo group.
Although these findings seemed promising, trial authors were careful to note that ProTECT II was conducted only at one site, with a 4:1 treatment:placebo ratio, and functional outcomes and mortality were evaluated only at 30 days postinjury using very limited, mostly qualitative tests that, as noted by a National Institutes of Health (NIH) expert consensus panel, “can miss clinically important findings that may be detectable by more sophisticated neuropsychological tests” ( ). It is worth noting also that the primary purpose of this first trial was to assess safety, not efficacy. ProTECT II did not study any biomarkers or any dose escalation, duration-of-treatment, or treatment-delay parameters.
Shortly after ProTECT II was started, a Phase II, 1:1 randomized trial performed at a hospital in Hangzhou, China ( ) began enrolling 159 male and female adult patients with only severe TBI (GCS 3–8). Blinded treatment with progesterone or vehicle was given by intramuscular injection in camellia oil vehicle. Patients in the progesterone group received 1.0 mg/kg within 8 h after injury and then once per 12 h for five consecutive days (2 mg/kg/day).
This was a much lower dose than that used in the ProTECT II trial ( Table 1.1 ). As with the US trial, no dose escalation, duration of treatment, or timing of treatment initiation was evaluated. On average, the patients received treatment within the first 4 h after their injuries. Neurological deficits were measured by the GOS, dichotomized into favorable or unfavorable outcomes. For their functional outcome measures the Chinese investigators used the Functional Independence Measure (FIM) scale and mortality at 3 and 6 months postinjury.
As with ProTECT II, no SAEs were attributable to the progesterone treatments during the time the patients were in the hospital. The investigators obtained a 6-month follow-up in 84% of the patients and found that mortality was significantly lower for the progesterone group (18% vs. 32%). In addition, at both 3- and 6-month follow-ups, the patients treated with progesterone were reported to have significantly better dichotomized GOS and FIM scores than the controls.
While their protocols were different in a number of respects, each of the two studies had limitations that the authors noted in their publications. Nonetheless, the results of the Phase II trials were taken to indicate that at 1 month (ProTECT II) and 3 and 6 months after injury (the Xiao et al. trial), TBI patients given progesterone treatments had lower mortality than controls. In ProTECT II, GOS scores were improved at 1 month, but only in the moderately injured patients, but in the Chinese trial better functional outcomes were noted in the severely injured patients at both 3 and 6 months after injury.
The Phase III Trials
With these findings in hand and with no other acute-stage pharmacological treatments for TBI available at the time, two independent, FDA-approved, national and international, multicenter Phase III trials were started with the expectation that the promising Phase II results would lead to successful outcomes in Phase III testing. ProTECT III, sponsored by NIH/NINDS, was a double-blind, two-arm, 1:1, 49-center trial planned to enroll ∼1200 patients with moderate-to-severe acute TBI with GCS scores of 4–12 ( ) (see Table 1.2 ).
| ProTECT III a NCT00822900 | SYNAPSE b NCT01143064 | |
|---|---|---|
| Centers | 49 | 180 |
| Geographic range | United States | 21 countries in Asia, Europe, North and South America |
| Planned enrollment | 1140 | 1180 |
| Patients screened | 17,681 | 10,519 |
| Final enrollment | 882 | 1195 |
| Percent male | 73.7 | 78.6 |
| PROG: 73.3 | PROG: 78.5 | |
| Placebo: 74.1 | Placebo: 78.7 | |
| Waiver of consent | Exemption from informed consent. Consent taken when legally authorized representative was available | No Written informed consent was obtained from a legally acceptable representative before randomization |
| Admission criteria: Diagnosis | Moderate-to-severe GCS 4–12 | Severe nonpenetrating TBI GCS 3–8; Marshall score ≥ II |
| Admission criteria: Age range | >18 (actual, 17–94) | 16–70 |
| Average/median patient age | PROG: 36 Placebo: 34 | PROG: 35 Placebo: 34 |
| Time to start of treatment | ≤4 h | ≤8 h |
| Study Design | ||
| Double-blind | ✓ | ✓ |
| Two-arm | ✓ | ✓ |
| Randomization | 1:1 | 1:1 |
| Effect sought | 10% absolute difference in outcome between treatment and control | 10% improvement in outcome at a two-tailed significance level of p < .01 |
| Primary outcome measures | GOS-E at 6 months (±30 days) | GOS at 6 months |
| Secondary outcome measures | Mortality DRS SAEs | GOS-E at 3 months Mortality at 1 and 6 months |
| Protocols | ||
| Vehicle/placebo | Fat emulsion (Intralipid 20%) | Proprietary lipid emulsion: 6% soybean oil and 1.2% egg lecithin |
| Time to initial dose | Within 4 h of injury | Within 8 h of injury |
| Drug preparation | Study-drug kits prepared by principal drug service site shipped to site pharmacists who by mixing a weight-based dose prepared the coded kit assigned by the randomization algorithm | Drug and placebo were coded and shipped ready-to-use to the hospitals. There was no mixing onsite |
| Test drug/vehicle administration | Total infusion time 96 h (0.714 mg/kg/1 h followed by 0.5 mg/kg/71 h followed by 24 h taper) | Total infusion time 120 h (0.71 mg/kg for 1 h followed by 0.50 mg/kg/h for 119 h) |
| Findings | ||
| Mortality (%) | PROG: 18.8; placebo: 15.7 | PROG: 22.2; placebo: 22.3 |
| Favorable primary outcome (%) | PROG: 51.0% c Placebo: 55.5% c | PROG: 50.4 placebo: 50.5 |
| SAEs due to treatment | None | None |
| Blood levels of PROG | Not reported | Median 335 ng/mL 2 days after initial dose |
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