U.S. patent application number 11/909278 was filed with the patent office on 2009-12-31 for methods for the treatment of a traumatic central nervous system injury.
This patent application is currently assigned to Emory University. Invention is credited to Stuart Hoffman, Arthur Kellermann, Douglas Lowery-North, Donald Stein, David Wright.
Application Number | 20090325920 11/909278 |
Document ID | / |
Family ID | 36987966 |
Filed Date | 2009-12-31 |
United States Patent
Application |
20090325920 |
Kind Code |
A1 |
Hoffman; Stuart ; et
al. |
December 31, 2009 |
METHODS FOR THE TREATMENT OF A TRAUMATIC CENTRAL NERVOUS SYSTEM
INJURY
Abstract
Methods of treating a subject with a traumatic central nervous
system injury, more particularly, a traumatic brain injury, are
provided. The methods comprise a therapy comprising a constant or a
two-level dosing regime of progesterone. In one method, a subject
in need thereof is administered at least one cycle of therapy,
wherein the cycle of therapy comprises administering a
therapeutically effective two-level intravenous dosing regime of
progesterone. The two-level dosing regime comprises a first time
period, wherein a higher hourly dose of progesterone is
administered to the subject, followed by a second time period,
wherein a lower hourly dose of progesterone is administered to the
subject.
Inventors: |
Hoffman; Stuart; (Atlanta,
GA) ; Kellermann; Arthur; (Atlanta, GA) ;
Stein; Donald; (Atlanta, GA) ; Wright; David;
(Atlanta, GA) ; Lowery-North; Douglas; (Atlanta,
GA) |
Correspondence
Address: |
FOLEY AND LARDNER LLP;SUITE 500
3000 K STREET NW
WASHINGTON
DC
20007
US
|
Assignee: |
Emory University
Atlanta
GA
|
Family ID: |
36987966 |
Appl. No.: |
11/909278 |
Filed: |
March 24, 2006 |
PCT Filed: |
March 24, 2006 |
PCT NO: |
PCT/US2006/010797 |
371 Date: |
September 11, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60664728 |
Mar 24, 2005 |
|
|
|
60729663 |
Oct 24, 2005 |
|
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Current U.S.
Class: |
514/177 |
Current CPC
Class: |
A61P 25/00 20180101;
A61P 9/00 20180101; A61P 25/28 20180101; A61K 31/57 20130101 |
Class at
Publication: |
514/177 |
International
Class: |
A61K 31/57 20060101
A61K031/57; A61P 25/28 20060101 A61P025/28; A61P 25/00 20060101
A61P025/00 |
Goverment Interests
FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
[0001] This invention was made with United States Government
support under 1R01 N5 39097-01 A1 awarded by the National Institute
of Neurological Disorders and Stroke (NIDS), National Institute of
Health. The United States Government has certain rights in the
invention.
Claims
1. A method of treating a traumatic brain injury in a human
subject, said method comprising administering to said subject in
need thereof at least one cycle of therapy, wherein said cycle of
therapy comprises administering a therapeutically effective
two-level intravenous dosing regime of progesterone, said two-level
dosing regime comprising a first time period, wherein a higher
hourly infusion dose of progesterone is administered to the
subject, followed by a second time period, wherein a lower hourly
infusion dose of progesterone is administered to said subject.
2. The method of claim 1, wherein the first time period comprises
an infusion dose of progesterone of about 0.1 mg/kg/hr to about 7.1
mg/kg/hr.
3. The method of claim 2, wherein the first time period comprises
an infusion dose of progesterone of about 0.71 mg/kg/hr.
4. The method of claim 1, wherein the second time period comprises
an infusion dose of progesterone of about 0.05 mg/kg/hr to about 5
mg/kg/hr.
5. The method of claim 4, wherein the second time period comprises
an infusion dose of about 0.5 mg/kg/hr.
6. The method of claim 1, wherein the second time period comprises
about a 24 hour to about a 120 hour period.
7. The method of claim 6, wherein the second time period comprises
about a 71 hour period.
8. The method of claim 1, wherein the first time period comprises
an infusion dose of progesterone of about 0.71 mg/kg/hr, the second
time period comprises an infusion dose of about 0.5 mg/kg/hr, the
first time period comprises about 1 hour, and the second time
period comprises about a 71 hour period.
9. The method of claim 1, wherein the two-level intravenous dosing
regime of progesterone results in a progesterone serum level in
said subject of about 100 ng/ml to about 2000 ng/ml.
10. The method of claim 9, wherein the progesterone serum level is
about 350 ng/ml to about 450 ng/ml.
11. The method of claim 1, further comprising a third time period,
wherein said third time period comprises a tapered administration
of the progesterone to the subject.
12. The method of claim 1, wherein the first and the second time
periods are continuous.
13. The method of claim 1, wherein the first and the second time
periods are discontinuous.
14. The method of claim 1, wherein said first time period comprises
a bolus injection.
Description
FIELD OF THE INVENTION
[0002] The invention relates to methods for treating a traumatic
injury to the central nervous system.
BACKGROUND OF THE INVENTION
[0003] Between 1.5 and 2 million Americans sustain a traumatic
brain injury (TBI) each year (Anonymous, "Traumatic Brain Injury,"
Center for Disease Control and Prevention, National Center for
Injury Prevention and Control, 2003, Vol. 2003). In the U.S. it is
estimated that TBI is responsible for 50,000 deaths and 100,000
hospitalizations annually (Anonymous, "Traumatic Brain Injury,"
Center for Disease Control and Prevention, National Center for
Injury Prevention and Control, 2003, Vol. 2003). Over 80,000 are
disabled annually, approximately 17,000 of whom require specialized
care for life (Kraus (1997) "Epidemiology of Head Injury," in Head
Injury, ed. Cooper (Williams & Wilkins Co., Baltimore) pp 1-19;
Selecki et al. (1982) Australian & New Zealand Journal of
Surgery 52(1):93-102). In addition to the initial lesion created by
abrupt trauma to the brain, excessive biomechanical force initiates
a cascade of secondary deleterious events that can dramatically
increase lesion size, morbidity, and mortality for days to months
after the initial injury (McIntosh et al. (1996) Lab Invest,
74(2):315-42; Stambrook et al. (1990) Can J Surg 33(2):115-8).
Despite the enormity of the problem, an effective pharmacological
treatment for TBI in humans has not been identified.
[0004] Continuous intravenous (IV) infusion allows rapid drug
delivery and achievement of a continuous steady state serum
concentration, but this route for administration of progesterone is
not FDA approved in the United States. Only three human studies
involving the use of IV progesterone in the US have been reported.
In an FDA-approved (IND 33,580) phase I clinical trial, Christen,
et al. administered IV progesterone dissolved in an
ethanol-Intralipid 20% fat emulsion combined with doxorubicin over
24 hours to 32 cancer patients without toxic effects (Christen et
al. (1993) Journal of Clinical Oncology 11(12):2417-2426). In a
second study, Allolio et al. reported that steady state serum
concentrations (C.sub.SS) of progesterone could be achieved in
healthy male volunteers (Allolio et al. (1995) European Journal of
Endocrinology 133(6):696-700). The third study was modeled after
the study performed by Christen et al, but was a phase II trial
testing the effect of coadministration of high-dose progesterone on
the pharmacokinetics of paclitaxel. The manuscript did not present
detailed information on the pharmacokinetics of progesterone.
[0005] Following a traumatic injury to the central nervous system,
a cascade of physiological events leads to neuronal loss including,
for example, an inflammatory immune response and excitotoxicity
resulting from the initial impact disrupting the glutamate,
acetylcholine, cholinergic, GABA.sub.A, and NMDA receptor systems.
In addition, the traumatic CNS injury is frequently followed by
brain and/or spinal cord edema that enhances the cascade of injury
and leads to further secondary cell death and increased patient
mortality. Methods are needed for the in vivo treatment of
traumatic CNS injuries that are successful at providing subsequent
trophic support to remaining central nervous system tissue, and
thus enhancing functional repair and recovery, under the complex
physiological cascade of events which follow the initial
insult.
SUMMARY OF THE INVENTION
[0006] Methods of treating a subject with a traumatic central
nervous system injury, more particularly, a traumatic brain injury,
are provided. The methods comprise a therapy comprising a constant
or a two-level dosing regime of progesterone or synthetic
progestin.
[0007] Further provided is a method of treating a traumatic brain
injury in a human subject. The method comprises administering to
the subject in need thereof at least one cycle of therapy, wherein
the cycle of therapy comprises administering a therapeutically
effective two-level intravenous dosing regime of progesterone or
synthetic progestin. The two-level dosing regime can comprise a
first time period, wherein a higher hourly dose of progesterone or
synthetic progestin is administered to the subject, followed by a
second time period, wherein a lower hourly dose of progesterone or
synthetic progestin is administered to the subject. In specific
methods, the first time period comprises an hourly dose of
progesterone or synthetic progestin of about 0.1 mg/kg to about 7.1
mg/kg. In other methods, the second time period comprises an hourly
dose of progesterone or synthetic progestin of about 0.05 mg/kg to
about 5 mg/kg. In other methods, a third time period comprising a
tapered administration protocol is added to the progesterone or
synthetic progestin dosing regime.
BRIEF DESCRIPTION OF THE DRAWINGS
[0008] FIG. 1 shows stable progesterone concentrations can be
achieved rapidly using continuous intravenous infusion. The closed
circles represent the serum concentration-time profile for one
patient receiving progesterone. The solid triangles represent the
serum concentration-time profile for a patient receiving a placebo
infusion. Progesterone concentrations for patients receiving a
placebo infusion remained constant throughout the study period.
C.sub.SS concentrations in patients receiving progesterone are
rapidly reached and, once achieved, are stable throughout the
infusion period.
[0009] FIG. 2 shows there is a significant correlation between
predicted and measured C.sub.SS. C.sub.ss were predicted as the
ratio of infusion rate and CL. The predicted values were compared
to C.sub.SS measured for each patient by plotting each pair of
values against the line of identity. The Spearman Rank correlation
coefficient for this relationship was 0.946 (p<0.001).
[0010] FIG. 3 shows bland-Altman analysis of the correlation
between predicted and measured C.sub.SS. Because a plot of
predicted versus measured C.sub.SS often do not reveal a systematic
under or over estimation (bias), a Bland-Altman analysis was
conducted. The averages of the measured and predicted values
(abcissa) are plotted against the relative difference in the two
values (ordinate). The solid line is the mean value for the
relative difference (-0.8.+-.12.2%; mean.+-.SD) and the dotted
lines represent the 95% confidence intervals for the data. This
plot clearly demonstrates that there is no significant bias
associated with this method of prediction.
[0011] FIG. 4 shows C.sub.SS values a consistently lower than those
predicted based on previously reported pharmacokinetic parameters.
Measured C.sub.SS for the 21 males (solid circles) and 11 females
(solid triangles) are individually plotted. The solid and dotted
lines represent our original target concentrations of 450.+-.100
ng/mL. These data clearly demonstrate that in TBI patients,
C.sub.SS values are significantly lower than predicted using
pharmacokinetic parameters previously reported.
[0012] FIG. 5 provides a schematic of the enrollment protocol for
the selection of patient for the TBI study.
DETAILED DESCRIPTION OF THE INVENTION
[0013] The present inventions now will be described more fully
hereinafter with reference to the accompanying drawings, in which
some, but not all embodiments of the inventions are shown. Indeed,
these inventions may be embodied in many different forms and should
not be construed as limited to the embodiments set forth herein;
rather, these embodiments are provided so that this disclosure will
satisfy applicable legal requirements. Like numbers refer to like
elements throughout.
[0014] Many modifications and other embodiments of the inventions
set forth herein will come to mind to one skilled in the art to
which these inventions pertain having the benefit of the teachings
presented in the foregoing descriptions and the associated
drawings. Therefore, it is to be understood that the inventions are
not to be limited to the specific embodiments disclosed and that
modifications and other embodiments are intended to be included
within the scope of the appended claims. Although specific terms
are employed herein, they are used in a generic and descriptive
sense only and not for purposes of limitation.
[0015] The present invention relates to methods of treating a human
subject with a traumatic central nervous system injury, more
particularly, a traumatic brain injury. As discussed in more detail
below, the methods comprise a therapy comprising a dosing regime of
progesterone or synthetic progestin.
[0016] A traumatic injury to the CNS is characterized by a physical
impact to the central nervous system. For example, a traumatic
brain injury results when the brain is subjected to a physical
force that results in progressive neuronal cell damage and/or cell
death. A traumatic brain injury may result from a blow to the head
and manifest as either an open or closed injury. Severe brain
damage can occur from lacerations, skull fractures, and conversely,
even in the absence of external signs of head injury. Accordingly,
the methods of the invention can be used to treat a traumatic brain
injury, including blunt traumas, as well as, penetrating
traumas.
[0017] The physical forces resulting in a traumatic brain injury
may cause their effects by inducing three types of injury: skull
fracture, parenchymal injury, and vascular injury. Parenchymal
injuries include concussion, direct parenchymal injury and diffuse
axonal injury. Concussions are characterized as a clinical syndrome
of alteration of consciousness secondary to head injury typically
resulting from a change in the momentum of the head (movement of
the head arrested against a ridged surface). The pathogenesis of
sudden disruption of nervous activity is unknown, but the
biochemical and physiological abnormalities that occur include, for
example, depolarization due to excitatory amino acid-mediated ionic
fluxes across cell membranes, depletion of mitochondrial adenosine
triphosphate, and alteration in vascular permeability.
Postconcussive syndrome may show evidence of direct parenchymal
injury, but in some cases there is no evidence of damage.
[0018] Contusion and lacerations are conditions in which direct
parenchymal injury of the brain has occurred, either through
transmission of kinetic energy to the brain and bruising analogous
to what is seen in soft tissue (contusion) or by penetration of an
object and tearing of tissue (laceration). A blow to the surface of
the brain leads to rapid tissue displacement, disruption of
vascular channels, and subsequent hemorrhage, tissue injury and
edema. Morphological evidence of injury in the neuronal cell body
includes pyknosis of nucleus, eosinophilia of the cytoplasm, and
disintegration of the cell. Furthermore, axonal swelling can
develop in the vicinity of damage neurons and also at great
distances away from the site of impact. The inflammatory response
to the injured tissue follows its usual course with neutrophiles
preceding the appearance of macrophages.
[0019] In accordance with the methods of the present invention,
progesterone or synthetic progestin is used to promote a positive
therapeutic response with respect to the traumatic central nervous
system injury. By "treatment" is intended any improvement in the
subject having the traumatic CNS injury including both improved
morphological recovery (i.e., enhanced tissue viability) and/or
behavioral recovery. The improvement can be characterized as an
increase in either the rate and/or the extent of behavioral and
anatomical recovery following the traumatic CNS injury.
Accordingly, a "positive therapeutic response" includes both a
complete response and a partial response. Various methods to
determine if a complete or a partial therapeutic response has
occurred are discussed in detail elsewhere herein.
[0020] Neurodegeneration is the progressive loss of neurons in the
central nervous system. As used herein, "neuroprotection" is the
arrest and/or reverse progression of neurodegeneration following a
traumatic central nervous system injury. Multiple physiological
events lead to the neurodegeneration of the CNS tissues following a
traumatic CNS injury. These events include, for example, cerebral
edema, destruction of vascular integrity, increase in the immune
and inflammatory response, demyelinization, and lipid peroxidation.
Hence, the methods of the invention also find use in reducing
and/or preventing the physiological events leading to
neurodegeneration. Specifically, the present invention provides
methods for reducing or eliminating neuronal cell death, edema,
ischemia, and enhancing tissue viability following a traumatic
injury to the central nervous system.
[0021] The progesterone or synthetic progestin therapy of the
invention is administered to a subject having a traumatic CNS
injury. As defined herein, the subject can be any mammal,
preferably a human. In specific embodiments, the human is an adult
(over 18 years of age), while in other embodiments, the human is a
child (under 18 years of age). The child can be an neonate, infant,
toddler, pre-pubescent or post-pubescent and range in age from
about birth, 1 month to about 2 year, about 1 year to about 5
years, about 4 years to about 9 years, about 8 years to about 14,
or about 13 to about 18 years of age. In addition, the human can be
about 55 to 60, 60 to 65, 65 to 70, 70 to 75, 75 to 80, 80 to 85,
85 to 90, 90 to 95 or older.
[0022] The present invention provides a method of treating a
traumatic CNS injury by administering to a subject progesterone or
synthetic progestin in a therapeutically effective amount. By
"therapeutically effective amount" is meant the concentration of a
progesterone or synthetic progestin that is sufficient to elicit a
therapeutic effect. Thus, the concentration of a progesterone or
synthetic progestin in an administered dose unit in accordance with
the present invention is effective in the treatment or prevention
of neuronal damage that follows a traumatic injury to the CNS and
hence, elicits a neuroprotective effect. The therapeutically
effective amount will depend on many factors including, for
example, the specific activity of the progesterone or synthetic
progestin, the severity and pattern of the traumatic injury, the
resulting neuronal damage, the responsiveness of the patient, the
weight of the patient, along with other intraperson variability,
the method of administration, and the progesterone or synthetic
progestin formulation used.
[0023] The compositions comprising the therapeutically effective
concentration of progesterone or synthetic progestin may be
administered using any acceptable method known in the art. Thus,
for example, the pharmaceutical composition comprising progesterone
or synthetic progestin can be administered by any method, including
intravenous (IV) injection, intramuscular (IM) injection,
subcutaneous (SC) injection, or vaginal administration. In specific
embodiments of the invention, the pharmaceutical composition
comprising progesterone or synthetic progestin is administered by
IV injection. When administered intravenously, the pharmaceutical
composition comprising the progesterone or synthetic progestin can
be administered by infusion over a period of about 1 to about 120
hours. In some embodiments, infusion of the progesterone or
synthetic progestin occurs over a period of about 24 to about 72
hours, over a period of about 48 to about 96 hours, or over a
period of about 24 to about 120 hours.
[0024] In one embodiment of the present invention, progesterone or
synthetic progestin is administered via parenteral administration
in a dose of about 0.1 ng to about 100 g per kg of body weight,
about 10 ng to about 50 g per kg of body weight, from about 100 ng
to about 1 g per kg of body weight, from about 1 .mu.g to about 100
mg per kg of body weight, from about 1 .mu.g to about 50 mg per kg
of body weight, from about 1 mg to about 500 mg per kg of body
weight; and from about 1 mg to about 50 mg per kg of body weight.
Alternatively, the amount of progesterone or synthetic progestin
administered to achieve a therapeutic effective dose is about 0.1
ng, 1 ng, 10 ng, 100 ng, 1 .mu.g, 10 .mu.g, 100 .mu.g, 1 mg, 2 mg,
3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13
mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 30 mg, 40 mg,
50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 500 mg per kg of body
weight or greater.
[0025] Progesterone or synthetic progestin may be administered once
or several times a day. The duration of the treatment may be once
per day for a period of about 1, 2, 3, 4, 5, 6, 7 days or more. The
daily dose can be administered either by a single dose in the form
of an individual dosage unit or several smaller dosage units or by
multiple administration of subdivided dosages at certain
intervals.
[0026] For instance, a dosage unit can be administered from about 0
hours to about 1 hr, about 1 hr to about 24 hr, about 1 to about 72
hours, about 1 to about 120 hours, or about 24 hours to at least
about 120 hours post injury. Alternatively, the dosage unit can be
administered from about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,
13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 30, 40, 48, 72, 96,
120 hours or longer post injury. Subsequent dosage units can be
administered any time following the initial administration such
that a therapeutic effect is achieved. For instance, additional
dosage units can be administered to protect the subject from the
secondary wave of edema that may occur over the first several days
post-injury.
[0027] In specific embodiments of the invention, the subject
undergoing the therapy with progesterone or synthetic progestin is
administered a constant progesterone or synthetic progestin dosing
regimen. By "constant progesterone or synthetic progestin dosing
regimen" is intended the subject undergoing therapy with
progesterone or synthetic progestin is administered a constant
total hourly infusion dose of progesterone or synthetic progestin
over the course of treatment. This hourly dose of progesterone or
synthetic progestin is partitioned into a series of equivalent
doses that are administered according to an appropriate dosing
schedule depending on the method of administration. The duration of
the constant progesterone or synthetic progestin dosing regimen is
about 12, 24, 36, 60, 72, 84, or 120 hours or about 1 to 24 hours,
about 12 to 36 hours, about 24 to 48 hours, about 36 to 60 hours,
about 48 to 72 hours, about 60 to 96 hours, about 72 to 108 hours,
about 96 to 120 hours, or about 108 to 136 hours.
[0028] In other embodiments of the invention, the therapy with the
progesterone or synthetic progestin comprises a "two-level
progesterone or synthetic progestin dosing regimen." By "two-level
progesterone or synthetic progestin dosing regimen" is intended the
subject undergoing the therapy with progesterone or synthetic
progestin is administered progesterone or synthetic progestin
during two time periods of progesterone or synthetic progestin
dosing. The two-time periods can have a combined duration of about
12 hours to about 7 days, including, 1, 2, 3, 4, or 5 days or about
15, 15, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95,
100, 105, 110, 115, 120, 125, 130, 135, 140, or 144 hours or about
1 to 24 hours, about 12 to 36 hours, about 24 to 48 hours, about 36
to 60 hours, about 48 to 72 hours, about 60 to 96 hours, about 72
to 108 hours, about 96 to 120 hours, or about 108 to 136 hours. In
one embodiment, the two-level progesterone or synthetic progestin
dosing regimen has a combined duration of about 1 day to about 5
days; in other embodiments, the two-level progesterone or synthetic
progestin dosing regimen has a combined duration of about 1 day to
about 3 days.
[0029] In one embodiment, the total hourly dose of progesterone or
synthetic progestin that is to be administered during the first and
second time periods of the two-level progesterone or synthetic
progestin dosing regimen is chosen such that a higher total
infusion dose of progesterone or synthetic progestin per hour is
given during the first time period and a lower infusion dose of
progesterone or synthetic progestin per hour is given during the
second time period. The duration of the individual first and second
time periods of the two-level progesterone or synthetic progestin
dosing regimen can vary, depending upon the health of the
individual and history of the traumatic injury. Generally, the
subject is administered higher total infusion dose of progesterone
or synthetic progestin per hour for at least 1, 2, 3, 4, 5, 6, 12
or 24 hours out of the 1 day to 5 day two-level progesterone or
synthetic progestin dosing regimen. The length of the second time
period can be adjusted accordingly, and range for example, from
about 12 hrs, 24 hrs, 36 hrs, 48 hrs, 60 hrs, 72 hrs, 84 hrs, 96
hrs, 108 hrs, 120 hrs or about 12 to about 36 hrs, about 24 to
about 36 hrs, about 24 to about 48 hrs, about 36 hrs to about 60
hours, about 48 hrs to about 72 hrs, about 60 hrs to about 84
hours, about 72 hrs to about 96 hrs, or about 108 hrs to about 120
hrs. Thus, for example, where the two-level progesterone or
synthetic progestin dosing regimen has a combined duration of 3
days, the higher total doses of progesterone or synthetic progestin
could be administered for the first hour, and the lower total
hourly dose of progesterone or synthetic progestin could be
administered for hours 2 to 72.
[0030] Though specific dosing regimens arc disclosed herein below,
it is recognized that the invention encompasses any administration
protocol that provides for a two-level progesterone or synthetic
progestin dosing regimen that provides for initial exposure to
higher hourly doses of progesterone or synthetic progestin, and
subsequent exposure to a lower hourly doses of progesterone or
synthetic progestin. For example, the first progesterone or
synthetic progestin dosing regime can be administered by a single
bolus injection, followed by a second time period of progesterone
or synthetic progestin IV administration.
[0031] In still further embodiments, the total infusion dose of
progestrone per hour that is to be administered during the first
and second time periods of the two-level progesterone or synthetic
progestin dosing regimen is chosen such that a lower total hourly
dose of progesterone or synthetic progestin is given during the
first time period and a higher hourly dose of progesterone or
synthetic progestin is given during the second time period.
[0032] Area under the curve (AUC) refers to the area under the
curve that tracks the serum concentration (nmol/L) of progesterone
or synthetic progestin over a give time following the IV
administration of the reference progesterone or synthetic progestin
standard. By "reference progesterone or synthetic progestin
standard" is intended the formulation of progesterone or synthetic
progestin that serves as the basis for determination of the total
hourly progesterone or synthetic progestin dose to be administered
to a human subject with a traumatic central nervous system injury
in accordance with the desired constant or two-level progesterone
or synthetic progestin dosing regimen to achieve the desired
positive effect, i.e., a positive therapeutic response that is
improved with respect to that observed without administration of
progesterone or synthetic progestin. For the determination of the
AUC for the reference progesterone or synthetic progestin standard,
see the Experimental Section, Example 1. Accordingly, the total
hourly dose of progesterone or synthetic progestin to be
administered during the constant or two-level progesterone or
synthetic progestin dosing regimen can therefore allow for a final
serum level of progesterone or synthetic progestin of about of
about 100 ng/ml to about 1000 ng/ml, about 1100 ng/ml to about 1450
ng/ml, 100 ng/ml to about 250 ng/ml, about 200 ng/ml to about 350
ng/ml, about 300 ng/ml to about 450 ng/ml, about 350 ng/ml to about
450 ng/ml, about 400 ng/ml to about 550 ng/ml, about 500 ng/ml to
about 650 ng/ml, about 600 ng/ml to about 750 ng/ml, about 700
ng/ml to about 850 ng/ml, about 800 ng/ml to about 950 ng/ml, about
900 ng/ml to about 1050 ng/ml, about 1000 ng/ml to about 1150
ng/ml, about 100 ng/ml to about 1250 ng/ml, about 1200 ng/ml to
about 1350 ng/ml, about 1300 ng/ml to about 1500 ng/m. In specific
embodiments, the serum level of progesterone or synthetic progestin
comprises about 100 ng/ml, 250 ng/ml, 300 ng/ml, 350 ng/ml, 360
ng/ml, 370 ng/ml, 380 ng/ml, 390 ng/ml, 400 ng/ml, 410 ng/ml, 420
ng/ml, 430 ng/ml, 440 ng/ml, 450 ng/ml, 500 ng/ml, 750 ng/ml, 900
ng/ml, 1200 ng/ml, 1400 ng/ml, or 1600 ng/ml.
[0033] The methods of the present invention also contemplate
embodiments where a subject undergoing a constant progesterone or
synthetic progestin therapy or a two-level progesterone or
synthetic progestin dosing regimen is given a time period off from
progesterone or synthetic progestin dosing. For example, when a
progesterone or synthetic progestin dosing regime is performed, the
time period off from progesterone or synthetic progestin can occur
between the conclusion of the first time period of the two-level
progesterone or synthetic progestin dosing regimen and the
initiation of the second time period of the two-level progesterone
or synthetic progestin dosing regimen. For example, one could
contemplate the first time period being administered in a
pre-hospital setting, for instance at the site of the trauma. The
second time period could then begin upon arrival at a hospital. In
these embodiments, the two-level progesterone or synthetic
progestin dosing regimen is interrupted such that progesterone or
synthetic progestin dosing is withheld for a period of about 15
minutes, 30 minutes, 1 hr, 2 hr, 3 hr, 4 hr, 5 hr, 6 hr Or
more.
[0034] In other embodiments, the constant progesterone or synthetic
progestin therapy or the two-level progesterone or synthetic
progestin therapy comprises a final time period in which the
administration of progesterone or synthetic progestin is tapered.
By "tapered administration" is meant an administration protocol
which reduces the dose of administration to the patient and thereby
produces a gradual reduction and eventual elimination of
progesterone or synthetic progestin, either over a fixed period of
time or a time determined empirically by a physician's assessment
based on regular monitoring of a therapeutic response of a subject
to a traumatic CNS injury. The period of the tapered progesterone
or synthetic progestin administration can be about 12, 24, 36, 48
hours or longer. Alternatively, the period of the tapered
progesterone or synthetic progestin administration can range from
about 1 to 12 hours, about 12 to about 48 hours, or about 24 to
about 36 hours.
[0035] The drug taper employed could be a "linear" taper. For
example, a "10%" linear taper from 500 mg would go 500, 450, 400,
350, 300, 250, 200, 150, 100, 50. Alternatively, an exponential
taper could be employed which, if the program outlined above is
used as an example, the exponential taper would be, e.g., 500, 450,
405, 365, 329, 296, 266,239, etc. Accordingly, about a 5%, 10%,
20%,30%, or 40% linear or exponential taper could be employed in
the methods of the invention. In addition, a linear or exponential
taper of about 1% to 5%, about 6% to 10%, about 11 % to 15%, about
16% to 20%, about 21% to 25%, about 26% to 30%, about 31% to 35%,
about 36% to 40% could be employed. Alternatively, the taper
schedule can be determined based on the physician's assessment of
the patient's response to therapy. Additional methods of tapered
administration can be found, for example, in U.S. Provisional
Application 60/729,663, filed Oct. 24, 2005, herein incorporated by
reference in its entirety.
[0036] Where a subject undergoing therapy in accordance with the
previously mentioned dosing regimens exhibits a partial response,
or a relapse following completion of the first cycle of the
therapy, subsequent courses of progesterone or synthetic progestin
therapy may be needed to achieve a partial or complete therapeutic
response. Thus, subsequent to a period of time off from a first
treatment period, which may have comprised a constant progesterone
or synthetic progestin dosing regimen or a two-level progesterone
or synthetic progestin dosing regimen, a subject may receive one or
more additional treatment periods comprising either constant or
two-level progesterone or synthetic progestin dosing regimens. Such
a period of time off between treatment periods is referred to
herein as a time period of discontinuance. It is recognized that
the length of the time period of discontinuance is dependent upon
the degree of subject response (i.e., complete versus partial)
achieved with any prior treatment periods of the progesterone or
synthetic progestin therapy.
[0037] These multiple treatment sessions are referred to herein as
maintenance cycles, where each maintenance cycle comprises a
completed constant or two-level progesterone or synthetic progestin
dosing regimen. By "completed two-level progesterone or synthetic
progestin dosing regimen" is intended the subject has been
administered both the first period and the second period of
progesterone or synthetic progestin dosing. The necessity for
multiple maintenance cycles can be assessed by monitoring the
physiological and behavioral improvement of the patient. The
duration between maintenance cycles can be about 1 hr, 15 hr, 1
day, 2 day, 3 day, 4 day, 5 day, 6 day or other such time periods
falling within the range of about 1 day to about 14 days.
[0038] The term "progesterone" as used herein refers to a member of
the progestin family and comprises a 21 carbon steroid hormone.
Progesterone is also known as D4-pregnene-3,20-dione;
.delta.4-pregnene-3,20-dione; or pregn-4-ene-3,20-dione and it its
structure is provided below as formula (I). The progesterone used
in the methods of the invention can be naturally occurring or
synthetic.
##STR00001##
[0039] Further encompassed by the methods of the invention are
synthetic progestins. As used herein a "synthetic progestin" is a
molecule whose structure is related to that of progesterone, is
synthetically derived, and retains the biologically activity of
progesterone (i.e., treats a traumatic CNS injury). Representative
synthetic progestin include, but are not limited to, modifications
that produce 17a-OH esters (i.e., 17.alpha.-hydroxyprogesterone
caproate), as well as, modifications that introduce
6.alpha.-methyl, 6-Me, 6-ene, and 6-chloro sustituents onto
progesterone (i.e., medroxyprogesterone acetate, megestrol acetate,
and chlomadinone acetate). Table 1 provides further, non-limiting
examples, of synthetic progestins.
TABLE-US-00001 TABLE 1 Classification of Synthetic Progestins
Classification Usual classification by generation* by structure
First Second Third Estranes Ethynodiol diacetate -- -- (with
ethinyl estradiol: Demulen) Norethindrone (Micronor) Norethindrone
acetate (Aygestin) Gonanes Norgestrel (Ovrette) Levonorgestrel
Desogestrel (with (Norplant; with ethinyl estradiol: Desogen)
ethinyl estradiol: Gestodene.dagger. Alesse, Nordette) Norgestimate
(with ethinyl estradiol: Ortho-Cyclen, Ortho Tri-Cyclen) Pregnanes
Medroxyprogesterone -- -- acetate (Provera) *The traditional
classification is based on time since market introduction and not
on structural and physiologic differences or efficacy.
[0040] The composition comprising progesterone or synthetic
progestin which is employed in the methods of the invention may
further comprise an inorganic or organic, solid or liquid,
pharmaceutically acceptable carrier. The carrier may also contain
preservatives, wetting agents, emulsifiers, solubilizing agents,
stabilizing agents, buffers, solvents and salts. Compositions may
be sterilized and exist as solids, particulants or powders,
solutions, suspensions or emulsions. In one embodiment, the
progesterone or synthetic progestin is dissolved in ethanol, or any
other carrier which allows progesterone or synthetic progestin to
dissolve.
[0041] The progesterone or synthetic progestin can be formulated
according to known methods to prepare pharmaceutically useful
compositions, such as by admixture with a pharmaceutically
acceptable carrier vehicle. Suitable vehicles and their formulation
are described, for example, in Remington's Pharmaceutical Sciences
(16th ed., Osol, A. (ed.), Mack, Easton Pa. (1980)). In order to
form a pharmaceutically acceptable composition suitable for
effective administration, such compositions will contain an
effective amount of the progesterone, either alone, or with a
suitable amount of carrier vehicle.
[0042] The pharmaceutically acceptable carrier of the present
invention will vary depending on the method of drug administration.
The pharmaceutical carrier employed may be, for example, either a
solid, liquid, or time release. Representative solid carriers are
lactose, terra alba, sucorse, talc, geletin, agar, pectin, acacia,
magnesium stearate, stearic acid, microcrystalin cellulose, polymer
hydrogels, and the like. Typical liquid carriers include syrup,
peanut oil, olive oil, cyclodextrin, intralipid, and the like
emulsions. Those skilled in the art are familiar with appropriate
carriers for each of the commonly utilized methods of
administration. Furthermore, it is recognized that the total amount
of progesterone or synthetic progestin administered as a
therapeutic effective dose will depend on both the pharmaceutical
composition being administered (i.e., the carrier being used) and
the mode of administration.
[0043] In one embodiment, the carrier comprises cyclodextrin. For
example, the formation can comprise progesterone or synthetic
progestin dissolved in a 22.5% 2-hydroxypropyl-.beta.-cyclodextrin
(Sigma). See, for example, Goss et al. (2003) Pharm. Biochem. and
Behavior 76:231-242, the contents of which is herein incorporated
by reference. In yet another embodiment, the carrier comprises
intralipid. In one embodiment, Intralipid.RTM. 20% (Fresenius Kabi
pharmaceuticals, Clayton, N.C.) is employed. The lipophilic
properties of Intralipid.RTM. 20% allow up to 4 gm of progesterone
or synthetic progestin per 1 liter of intralipid to be dissolved
into solution.
[0044] Administration of the progesterone or synthetic progestin
may be performed by many methods known in the art. The present
invention comprises all forms of dose administration including, but
not limited to, systemic injection, parenteral administration,
intravenous, intraperitoneal, intramuscular, transdermal, buccal,
subcutaneous and intracerebroventricular administration.
Alternatively, the progesterone or synthetic progestin may be
administered directly into the brain or cerebrospinal fluid by any
intracerebroventricular technique including, for example, lateral
cerebro ventricular injection, lumbar puncture or a surgically
inserted shunt into the cerebro ventricle of a patient. Methods of
administering may be by dose or by control release vehicles.
[0045] Additional pharmaceutical methods may be employed to control
the duration of action. Controlled release preparations may be
achieved by the use of polymers to complex or absorb the
progesterone or synthetic progestin. The controlled delivery may be
exercised by selecting appropriate macromolecules (for example,
polyesters, polyamino acids, polyvinyl pyrrolidone,
ethylene-vinylacetate, methylcellulose, carboxymethylcellulose, or
protamine sulfate). The rate of drug release may also be controlled
by altering the concentration of such macromolecules.
[0046] Another possible method for controlling the duration of
action comprises incorporating the therapeutic agents into
particles of a polymeric substance such as polyesters, polyamino
acids, hydrogels, poly(lactic acid) or ethylene vinylacetate
copolymers. Alternatively, it is possible to entrap the therapeutic
agents in microcapsules prepared, for example, by coacervation
techniques or by interfacial polymerization, for example, by the
use of hydroxymethyl cellulose or gelatin-microcapsules or
poly(methylmethacrylate) microcapsules, respectively, or in a
colloid drug delivery system, for example, liposomes, albumin,
microspheres, microemulsions, nanoparticles, nanocapsules, or in
macroemulsions. Such teachings are disclosed in Remington's
Pharmaceutical Sciences (1980).
[0047] In further embodiments of the present invention, at least
one additional neuroprotective agent can be combined with the
progesterone or synthetic progestin to enhance neuroprotection
following a traumatic CNS injury. Such agents include, for example,
compounds that reduce glutamate excitotoxicity and enhance neuronal
regeneration. Such agents may be selected from, but not limited to,
the group comprising growth factors. By "growth factor" is meant an
extracellular polypeptide-signaling molecule that stimulates a cell
to grow or proliferate. When the progesterone or synthetic
progestin is administered conjointly with other pharmaceutically
active agents, (i.e., other neuroprotective agents) even less of
the progesterone or synthetic progestin may be therapeutically
effective.
[0048] The progesterone or synthetic progestin may be administered
per se or in the form of a pharmaceutically acceptable salt. When
used in medicine, the salts of the progesterone or synthetic
progestin should be both pharmacologically and pharmaceutically
acceptable, but non-pharmaceutically acceptable salts may
conveniently be used to prepare the free active compound or
pharmaceutically acceptable salts thereof and are not excluded from
the scope of this invention. Such pharmacologically and
pharmaceutically acceptable salts can be prepared by reaction of a
progesterone or a synthetic progestin with an organic or inorganic
acid, using standard methods detailed in the literature. Examples
of pharmaceutically acceptable salts are organic acids salts formed
from a physiologically acceptable anion, such as, tosglate,
methenesulfurate, acetate, citrate, malonate, tartarate, succinate,
benzoate, etc. Inorganic acid salts can be formed from, for
example, hydrochloride, sulfate, nitrate, bicarbonate and carbonate
salts. Also, pharmaceutically acceptable salts can be prepared as
alkaline metal or alkaline earth salts, such as sodium, potassium,
or calcium salts of the carboxylic acid group.
[0049] Thus the present invention also provides pharmaceutical
formulations or compositions, both for veterinary and for human
medical use, which comprise the progesterone or synthetic progestin
or a pharmaceutically acceptable salt thereof with one or more
pharmaceutically acceptable carriers thereof and optionally any
other therapeutic ingredients, such as other neurotrophic agents.
The carrier(s) must be pharmaceutically acceptable in the sense of
being compatible with the other ingredients of the formulation and
not unduly deleterious to the recipient thereof.
[0050] The compositions include those suitable for oral, rectal,
topical, nasal, ophthalmic, or parenteral (including
intraperitoneal, intravenous, subcutaneous, or intramuscular
injection) administration. The compositions may conveniently be
presented in unit dosage form and may be prepared by any of the
methods well known in the art of pharmacy. All methods include the
step of bringing the active agent into association with a carrier
that constitutes one or more accessory ingredients. In general, the
compositions are prepared by uniformly and intimately bringing the
active compound into association with a liquid carrier, a finely
divided solid carrier or both, and then, if necessary, shaping the
product into desired formulations.
[0051] In one embodiment, micronize progesterone or synthetic
progestin is used. The micronization process decreases particle
size and enhances dissolution. Prometrian is one such example of a
micronized formulation of progesterone.
[0052] Compositions of the present invention suitable for oral
administration may be presented as discrete units such as capsules,
cachets, tablets, lozenges, and the like, each containing a
predetermined amount of the active agent as a powder or granules;
or a suspension in an aqueous liquor or non-aqueous liquid such as
a syrup, an elixir, an emulsion, a draught, and the like.
[0053] A tablet may be made by compression or molding, optionally
with one or more accessory ingredients. Compressed tablets may be
prepared by compressing in a suitable machine, with the active
compound being in a free-flowing form such as a powder or granules
which are optionally mixed with a binder, disintegrant, lubricant,
inert diluent, surface active agent or dispersing agent. Molded
tablets comprised with a suitable carrier may be made by molding in
a suitable machine.
[0054] A syrup may be made by adding the active compound to a
concentrated aqueous solution of a sugar, for example sucrose, to
which may also be added any accessory ingredient(s). Such accessory
ingredients may include flavorings, suitable preservatives, an
agent to retard crystallization of the sugar, and an agent to
increase the solubility of any other ingredient, such as polyhydric
alcohol, for example, glycerol or sorbitol.
[0055] Formulations suitable for parental administration
conveniently comprise a sterile aqueous preparation of the active
compound, which can be isotonic with the blood of the
recipient.
[0056] Nasal spray formulations comprise purified aqueous solutions
of the active agent with preservative agents and isotonic agents.
Such formulations are preferably adjusted to a pH and isotonic
state compatible with the nasal mucous membranes.
[0057] Formulations for rectal administration may be presented as a
suppository with a suitable carrier such as cocoa butter, or
hydrogenated fats or hydrogenated fatty carboxylic acids.
[0058] Ophthalmic formulations are prepared by a similar method to
the nasal spray, except that the pH and isotonic factors are
preferably adjusted to match that of the eye.
[0059] Topical formulations comprise the active compound dissolved
or suspended in one or more media such as mineral oil, petroleum,
polyhydroxy alcohols or other bases used for topical formulations.
The addition of other accessory ingredients as noted above may be
desirable.
[0060] Further, the present invention provides liposomal
formulations of the progesterone or synthetic progestin and salts
thereof The technology for forming liposomal suspensions is well
known in the art. When the progesterone or synthetic progestin or
salt thereof is an aqueous-soluble salt, using conventional
liposome technology, the same may be incorporated into lipid
vesicles. In such an instance, due to the water solubility of the
compound or salt, the compound or salt will be substantially
entrained within the hydrophilic center or core of the liposomes.
The lipid layer employed may be of any conventional composition and
may either contain cholesterol or may be cholesterol-free. When the
compound or salt of interest is water-insoluble, again employing
conventional liposome formation technology, the salt may be
substantially entrained within the hydrophobic lipid bilayer that
forms the structure of the liposome. In either instance, the
liposomes that are produced may be reduced in size, as through the
use of standard sonication and homogenization techniques. The
liposomal formulations containing the progesterone or synthetic
progestin or salts thereof, may be lyophilized to produce a
lyophilizate which may be reconstituted with a pharmaceutically
acceptable carrier, such as water, to regenerate a liposomal
suspension.
[0061] Pharmaceutical formulations are also provided which are
suitable for administration as an aerosol, by inhalation. These
formulations comprise a solution or suspension of the desired
progesterone or synthetic progestin or a salt thereof or a
plurality of solid particles of the compound or salt. The desired
formulation may be placed in a small chamber and nebulized.
Nebulization may be accomplished by compressed air or by ultrasonic
energy to form a plurality of liquid droplets or solid particles
comprising the compounds or salts.
[0062] In addition to the aforementioned ingredients, the
compositions of the invention may further include one or more
accessory ingredient(s) selected from the group consisting of
diluents, buffers, flavoring agents, binders, disintegrants,
surface active agents, thickeners, lubricants, preservatives
(including antioxidants) and the like.
[0063] Behavioral assays can be used to determine the rate and
extent of behavior recovery in response to the treatment. Improved
patient motor skills, spatial learning performance, cognitive
function, sensory perception, speech and/or a decrease in the
propensity to seizure may also be used to measure the
neuroprotective effect. Such functional/behavioral tests used to
assess sensorimortor and reflex function are described in, for
example, Bederson et al. (1986) Stroke 17:472-476, DeRyck et al.
(1992) Brain Res. 573:44-60, Markgraf et al. (1992) Brain Res.
575:238-246, Alexis et al. (1995) Stroke 26:2336-2346; all of which
are herein incorporated by reference. Enhancement of neuronal
survival may also be measured using the Scandinavian Stroke Scale
(SSS) or the Barthl Index.
[0064] The treatment of a traumatic brain injury can be monitored
by employing a variety of neurological measurements. For example, a
partial therapeutic responses can be monitored by determining if,
for example, there is an improvement in the subjects a) maximum
daily Glasgow Coma Score; b) duration of coma; 3) daily
intracranial pressure-therapeutic intensity levels; 4) extent of
cerebral edema/mass effect measured on serial CT scans; and, 5)
duration of ventilator support. A brief description of each of
these assays is provided below.
[0065] The Glasgow Coma Score (index GCS) is a reflection of the
depth of impaired consciousness and is best obtained following
initial resuscitation (oxygenation, rehydration and support of
blood pressure) but prior to use of sedating drugs, neuromuscular
blocking agents, or endotracheal intubation.
[0066] The duration of coma will be defined as the number of hours
from the time of injury that the subject is unable to purposefully
respond to commands or mechanical stimulation. For non-intubated
subjects, this equates to a GCS score of >8. For intubated
patients, this correlates with a GCS motor score of .gtoreq.5.
Duration of coma has been found to be predictive of functional
outcome (Uhler et al. (1994) Neurosurgery 34(1): 122-8; Jiang et
al. (1996) Brain Res 735(1): 101-7; and Gonzalez-Vidal et al.
(1998) Arch Med Res 29(2): 117-24). Time spent in a coma induced
pharmacologically for reasons other than brain injury should be
subtracted in the final analysis.
[0067] The intracranial pressure (ICP) of patients with severe TBI
is often monitored with an intracranial pressure device. Monitoring
ICP can provide a measure of cerebral edema. However, inherent
variability and analysis complexities due to therapeutic
interventions intended on lowering the ICP mire using ICP
measurements. To adjust for these interventions a therapeutic
intensity scale was developed. This scale, known as the Therapeutic
Intensity Level (TIL), measures treatment aggressiveness for
elevated ICPs (Allolio et al. (1995) European Journal of
Endocrinology 133(6): 696-700; Adashi et al. (1996) Reproductive
endocrinology, surgery, and technology Philadelphia:
Lippincott-Raven; and, Beers et al. eds. (1999) The Merck manual of
diagnosis and therapy. 17th ed., Merck Sharp & Dohme Research
Laboratories, Rahway, N.J.).
[0068] The extent of cerebral edema and mass effect can be
determined by CT scans. For example, the volume of focal lesions
can be measured. Mass lesions, either high-density or mixed-density
abnormalities, will be evaluated by measuring the area of the
abnormality as a region of interest, multiplying the area by the
slice thickness, and summing these volumes for contiguous slices
showing the same lesion. Each lesion will be measured three times,
and the mean volume will be entered. This technique has been shown
to be reliable (Garcia-Estrada et al. (1993) Brain Res 628(1-2):
271-8).
[0069] Intracerebral lesions can be further characterized by
location (frontal, temporal, parietal, occipital, basal ganglia, or
any combination). When an edematous zone is present, its volume
(the hypodense perimeter) can be measured and analyzed separately.
Midline shift will be measured using the septum pellucidum as the
midline structure. The ventricle-brain ratio (VBR) will be
calculated to quantify the degree of cerebral atrophy. Levin et al.
((1981) Archives of Neurology 38(10):623-9) found that the VBR had
satisfactory reliability across different examiners, and was
related both to the severity of acute injury and neurobehavioral
sequelae (Hoffman et al. (1994) J Neurotrauma 11(4): 417-31).
[0070] The duration of ventilator support will be defined as the
number of hours the patient receives positive pressure mechanical
ventilation (Uhler et al. (1994) Veurosurgery 34(1): 122-8; Jiang
et al. (1996) Brain Res 735(1): 101-7; and Gonzalez-Vidal et al.
(1998) Arch Med Res 29(2): 117-24). Time spent under ventilator
support for reasons other than brain injury will be subtracted in
the final analysis.
[0071] In addition to the neurological measurements discussed
above, a partial therapeutic response can also be assayed through
various functional and neuropsychological outcomes. Several
standardized measures of neuropsychological and functional
performance are known. For instance subjects may display an
improvement in the Glasgow Outcome Scale (GOS)/Glasgow Outcome
Scale Extender (GOSE) and/or in the Disability Rating Scale (DRS).
The Glasgow Outcome Score is one of the most widely used measures
of brain injury recovery in the world (Garcia-Estrada et al. (1999)
Int J Dev Neurosci 17(2): p. 145-51). Patients are classified into
one of five categories: death, persistent vegetative state, severe
disability, moderate disability, and good recovery. It is easy to
administer and score, and has a high degree of reliability and
validity.
[0072] The Disability Rating Scale (DRS) offers more precision than
the GOS for measuring outcomes of moderate brain injury (Goodman et
al. (1996) J Neurochem 66(5): 1836-44). The DRS consists of an
eight-item rating of arousal and awareness, daily living
activities, physical dependence, and employability (Vedder et al.
(1999) J Neurochem 72(6):2531-8). Inter-rater reliability for the
entire DRS is high (0.97 to 0.98).
[0073] The Functional Independence Measure (FIM) can be used to
assess physical and cognitive disability. It contains 18 items in
the following domains: self-care, sphincter control, mobility,
locomotion, communication, and social cognition (Baulieu (1997)
Mult Scler 3(2): 105-12). The FIM has demonstrated reliability and
validity as an outcome measure following moderate and severe TBI
(Jung-Testas et al. (1994) J Steroid Biochem Mol Biol 48(1):
145-54).
[0074] The Sickness Impact Profile is one method for measuring
self-perceived health status (Schumacher et al. (1995) Ciba Found
Symp 191: p.90-112 and Koenig et al. (1995) Science
268(5216):1500-3). It consists of 136 questions divided into 12
categories: sleep and rest, eating, work, home management,
recreation and pastimes, ambulation, mobility, body care and
movement, social interaction, alertness, behavior, emotional
behavior, and communication. It has been widely used across a
variety of diseases and injuries, including head injury (Thomas et
al. (1999) Spine 24:2134-8). Baseline SIP scores will reflect
pre-injury health status, while follow-up scores will examine
post-injury functioning.
[0075] Having now generally described this invention, the same will
be better understood by reference to certain specific examples
which are included herein for purposes of illustration only, and
are not intended to be limiting of the invention, unless
specified.
Experimental
Example 1
[0076] As a first step in assessing the applicability of
progesterone therapy in humans, we examined the effects of acute
TBI and extracranial trauma on the pharmacokinetics of PG given by
intravenous infusion. Multiple blood samples were obtained from 11
female and 21 male trauma patients receiving PG and 1 female and 3
male patients receiving placebo infusions for 72 h. Values for
C.sub.SS, CL, t.sub.1/2 and V.sub.d were obtained using
AUC.sub.(0-72) and post-infusion blood samples. C.sub.SS values
were 337.+-.135 ng/mL, which were significantly lower than the
target concentration of 45.+-.100 ng/mL. The lower C.sub.SS is
attributed to the CL, which was higher than anticipated. In
addition, t.sub.1/2 was longer and V.sub.d was higher than
anticipated. There were no significant gender differences in any of
these parameters. These changes are consistent with the
hyperkinetic changes associated with critical injury. Our results
demonstrate that stable PG concentrations can be rapidly achieved
following TBI.
Methods
Patient Selection:
[0077] This study was approved by the Institutional Review Board of
Emory University, the Drug Safety Monitoring Board (NINDS) and the
FDA (IND #58,986). After obtaining informed consent, thirty-six
patients meeting the inclusion criteria outlined as follows were
studied. Treatments were randomized using a 4:1
progesterone:placebo ratio. Inclusion criteria required that each
patient be .gtoreq.18 years old, have a closed head injury arising
from blunt trauma, have a moderate to severe brain injury (Index
Glasgow Coma Score (GCS) 4-12) and arrive in the Emergency
Department and obtain informed consent (from next-of-kin) in less
than 11 hours post injury. Exclusion criteria included:
non-survivable injury; no neurological activity (GCS 3); mild TBI
(Index GCS 13-15); unknown time of injury; severe intoxication
(ETOH .gtoreq.250 mg %); spinal cord injury with neuro-deficits;
cardiopulmonary arrest; status epilepticus on arrival; blood
pressure<90 systolic--on arrival or for .gtoreq.5 minutes in
duration prior to enrollment; hypoxia on arrival pO.sub.2<60--on
arrival or for .gtoreq.5 minutes in duration prior to enrollment;
females who were pregnant; active breast or reproductive organ
cancers; or known allergy to progesterone, or Intralipid.RTM.
components (egg yolk or soy oil).
Drug Preparation:
[0078] Solutions of study drug were prepared by the Investigational
Drug Service of Emory Healthcare as follows: Progesterone was
dissolved in 95% ethanol and filtered into sterile vials using a
0.2.mu. filter. Aliquots of each solution were assayed for final
concentration and sterility. Stock solutions of
progesterone/placebo were packaged in kits (A, B, C, D or E) that
matched the randomized treatment assignments. Each kit contained
six vials. Vial 1 contained 15 ml of progesterone or placebo which
was used to prepare the initial bolus and first infusion dose. The
remaining 5 vials contained 12 ml of progesterone or placebo for
the remaining infusions. Since progesterone is soluble only in
alcohol, the diluent used to compound the progesterone solution was
95% ethanol. The placebo kits were also formulated with 95%
ethanol. Because of the alcohol concentration, doses of study drug
were mixed with Intralipid.RTM. immediately prior to infusion. Each
infusion dose was administered over 12 hours and repeated every 12
hours for a total of 72 hours. After randomizing a patient, a
dosing worksheet based on body weight and final progesterone
concentration was used to determine the volume of vial #l required
to be diluted in Intralipid.RTM. for a standard loading infusion
rate (14 cc/hr) and the first 11 hr of the maintenance infusion (10
cc/hr). The dosing worksheet was also used to calculate the volume
of study medication to be diluted in Intralipid.RTM. for each of
the remaining infusion reservoirs at a standard rate of 10
cc/hr.
Stability of Progesterone Solutions.
[0079] For all stability testing, the method of Segall, et al. was
used with minor modifications (Segall, et al. (1999) Journal of
Pharmaceutical & Biomedical Analysis, 19(5):803-8). The method
was originally validated to assess the stability of
medroxyprogesterone acetate and estradiol valerate tablets. It is
an isocratic HPLC-UV method utilizing external standardization. A 5
micron, 4.6.times.250mm BDS-Hypersil C-18 column (Keystone
Scientific) was used and the analyses were completed on an Agilent
100 model HPLC system with photodiode array detector. The mobile
phase consisted of 40% 0.07M ammonium acetate buffer, pH 7.2 and
60% acetonitrile. Detection was at 247 nM. A check of system
suitability yielded 2769 plates per meter (minimum
requirement>2500) based on the progesterone peak and a relative
standard deviation (RSD) of 0.80% (minimum requirement 1.0% or
less). The tailing factor for the progesterone peak was 0.5.
Reproducibility as assessed by 10 injections of the same
preparation on multiple different days was always less that
10%.
[0080] For each assay, progesterone preparations were diluted 1 to
10 with ethanol and 1 .mu.L of this dilution was injected. Under
these conditions, progesterone eluted at roughly 3.5 minutes. A
five point standard curve was run with each analysis.
Drug Administration:
[0081] The progesterone study drug solution was infused at the
loading rate of 14 mLs/hr (0.71 mg/kg/h) for one hour, followed by
a decrease in infusion rate to 10 mLs/hr (0.5 mg/kg/h) for the
remaining 71 hours. Although Intralipid solutions containing
progesterone were found to be stable for a minimum of 24 hours,
reservoirs of study drug were prepared and changed every 12 hr
during the infusion period to minimize the risk of biological
contamination. Any interruptions in drug administration or other
deviations from the protocol were noted on a drug administration
flow sheet and taken into account when calculating the total number
of mg of progesterone actually administered to each patient.
Sampling Paradigm:
[0082] Nine (5 ml) samples were obtained at the following times
during the infusion: pre-infusion (0), 4, 6, 12, 24, 36, 48, 60,
and 72 hours. An additional five samples were obtained following
cessation of infusion at: 0.5, 1, 2, 4 and 8 hours. Samples were
allowed to clot, and then centrifuged After that, the serum was
removed and stored at -70.degree. C. until analyzed.
Serum Progesterone Analysis:
[0083] Serum progesterone concentrations were measured using the
Immulite.RTM. progesterone chemi-luminescent enzyme immunoassay by
the Immunology Laboratory of the Department of Pathology, Emory
University Hospital. The within and between day coefficients of
variation for the assay were both <10%. We confirmed the
accuracy of our assay by comparing the results of 9 samples over
the range 0.5 to 700 ng/mL assayed in our laboratory with those
assayed by a reference laboratory (The Nichols Institute, San Juan
Capistrano, Calif.).
Pharmacokinetic Analysis:
[0084] The primary pharmacokinetic parameter, CL, was estimated as
the ratio of the dose to area under the serum concentration-time
curve (AUC). AUC's were calculated using the linear trapezoidal
rule (Veng-Pedersen (1989) Clin Pharmacokinet, 17(6):424-40). The
elimination phase rate constant, k.sub.e, was calculated from the
serum concentration-time data following the termination of the
infusion using iterative non-linear regression (WinNonlin.RTM.,
Pharsight Corporation, Mountain View, Calif.). Volume of
Distribution was estimated as the ratio of CL and k.sub.e. C.sub.ss
was estimated as the ratio of Dose and CL. Actual C.sub.ss was
defined as the concentration achieved when the slope of the serum
concentration-time curve for three or more consecutive samples was
not different from zero.
Statistical Analysis:
[0085] A `t` test for repeated measures and a Spearman's rank
correlation coefficient were used to compare the progesterone
concentrations measured by our laboratory with those measured by
the Nichols Institute. Predicted C.sub.ss concentrations were
calculated as the ratio of the infusion rate/clearance. Differences
between predicted and measured Css were made using a `t` test for
repeated measures. A Bland-Altman analysis was conducted to assess
the magnitude of any bias associated with this approach (Bland and
Altman (1986) Lancet, 1(8476):307-10). Pharmacokinetic parameter
comparisons between male and female were accomplished using a `t`
test for independent means. A p value of less than 0.05 was
considered the minimum level for rejection of the null
hypothesis.
Results
[0086] Thirty-six patients were studied. Thirty-two (21 males and
11 females) received progesterone and four (3 males and 1 female)
received a placebo infusion. There were no significant differences
in the pre-infusion progesterone concentrations between females
(2.86.+-.1.37 ng/mL) and males (2.53.+-.1.73 ng/mL) (p<0.5).
Pre-infusion progesterone concentrations for the patients receiving
placebo were 2.1.+-.0.8 ng/mL and were not significantly different
from patients who received progesterone. In addition, these
pre-infusion values did not significantly change over the 84 hour
time course of the study. FIG. 1 is a representative serum
concentration-time profile for one patient receiving progesterone
and one patient receiving a placebo infusion and in whom a complete
sampling paradigm was possible. Progesterone concentrations for
patients receiving a placebo infusion remained constant throughout
the study period. C.sub.SS concentrations in patients receiving
progesterone were rapidly reached and, once achieved, were stable
throughout the infusion period. Complete peri- and post-infusion
sampling was only possible in 7/11 females and 10/21 males because
of the critical nature of the injuries sustained by the study
patients. C.sub.SS values in the current study were lower than
expected based on those reported for infusions of progesterone in
cancer patients (Christen et al. (1993) Journal of Clinical
Oncology 11(12):2417-2426).
[0087] Table 2 is a summary of the demographic and primary
pharmacokinetic data stratified by sex. There were no significant
differences between males and females with respect to any of the
parameters in Table 2 with the exception of body weight. As one
might expect, the mean body weight for the males (81.5.+-.16.2 kg)
was significantly greater (p<0.003) than that for the females
(63.9.+-.11.0 kg). Clearance (CL) values were calculated from the
total dose of progesterone infused and the AUC.sub.(0-72 h) rather
than from AUC.sub.(0-.infin.) because complete post-infusion blood
sampling was not possible in a number of the patients for medical
reasons. The mean value for CL was found to be 1.73.+-.0.72 L/kg/h
and was not different in males (1.66.+-.0.67 L/kg/h) and females
(1.88.+-.0.81 L/kg/h). Although a direct comparison is not possible
because we did not record heights in our patients and therefore
could not calculate body surface areas, CL values in the current
study are higher than expected from those reported for progesterone
infusions in cancer patients (Christen et al. (1993) Journal of
Clinical Oncology 11(12):2417-2426). Using the value for
progesterone CL from the current serum concentration-time data did
not result in any statistically significant differences between the
C.sub.ss values predicted by R.sub.o/CL (332.+-.121 ng/mL) and
those actually measured (337.+-.135 ng/mL) and were not different
for either males or females. FIG. 2 is a summary of measured and
predicted C.sub.ss values plotted against the line of identity. The
Spearman Rank correlation coefficient for this relationship was
0.946 (p<0.001). The significance of the relationship was
confirmed using a Bland-Altman analysis which revealed no
systematic bias between the measured and predicted C.sub.ss values.
The relative difference between predicted and measured C.sub.ss was
-0.8.+-.12.2% (mean.+-.SD) (See FIG. 3). FIG. 4 is a plot of
measured C.sub.ss for each patient showing these concentrations
were systematically lower than the target concentration range
predicted from previous studies (Christen et al. (1993) Journal of
Clinical Oncology 11(12):2417-2426; Allolio et al. (1995) European
Journal of Endocrinology 133(6):696-700). These data suggest that
in trauma patients with moderate to severely head injuries the
resulting hyperkinetic physiologic state results in a clinically
significant increase in progesterone clearance. These data suggest
that to achieve our target concentration of 45.+-.100 ng/mL, the
maintenance infusion rate should be increased from 0.5 mg/kg/h to
approximately 0.8 mg/kg/h.
[0088] The mean value for terminal half-life was found to be
1.78.+-.1.0 h. Once again, there were no differences between males
(1.60.+-.0.95 h) and females (2.03.+-.1.08 h) (p<0.4). These
values are somewhat longer than those reported in cancer patient,
(Christen et al. (1993) Journal of Clinical Oncology
11(12):2417-2426). Volumes of distribution (V.sub.d) in the current
study are higher than expected from previous reports because of the
elevation in CL and decrease in terminal elimination phase rate
constant. Although values for males tended to be lower, V.sub.d's
were not significantly different for males (3.76.+-.2.14 L/kg) and
females (5.76.+-.4.21 L/kg) (p<0.22).
TABLE-US-00002 TABLE 2 Individual progesterone pharmacokinetic
parameters in TBI patients. Css Css Corrected BW CL Vd Measured
Predicted Ro Patient Sex Age (kg) GCS (L/kg/h) t.sub.1/2 (h) (L/kg)
ng/mL ng/mL mg/kg/h 1 F 25 72 7 1.04 2.70 4.04 423 482 0.47 2 F 29
65 8 2.11 2.56 7.78 234 240 0.95 3 F 20 57 11 3.60 166 139 1.62 4 F
22 50 6 1.68 0.92 2.24 249 297 0.76 5 F 48 73 11 1.20 472 416 0.54
6 F 21 70 4 1.58 1.20 2.73 331 317 0.71 7 F 19 85 7 1.16 457 432
0.52 8 F 53 50 7 2.95 2.43 10.35 195 170 1.33 9 F 20 55 7 2.25 3.64
11.83 240 222 1.01 10 F 54 57 4 1.91 296 262 0.86 11 F 24 69 6 1.19
0.77 1.33 415 420 0.54 Mean .+-. 30 63.9 7* 1.88 2.03 5.76 316 309
0.85 SD 14 11.0 4-11** 0.81 1.08 4.21 110 115 0.37 1 M 52 75 6 1.37
1.14 2.25 412 366 0.61 2 M 24 70 8 3.84 0.73 4.05 123 130 1.73 3 M
47 93 12 0.93 563 538 0.42 4 M 25 70 11 1.55 345 323 0.70 5 M 23 80
6 0.98 3.30 4.67 499 510 0.44 6 M 29 70 12 1.07 1.77 2.73 368 467
0.48 7 M 20 65 10 2.10 2.78 8.43 238 238 0.95 8 M 18 59 6 2.04 1.70
5.01 248 245 0.92 9 M 62 66 6 1.33 2.20 4.22 400 376 0.60 10 M 76
84 7 1.55 332 322 0.70 11 M 33 100 4 2.33 225 215 1.05 12 M 25 87.7
6 1.36 268 368 0.61 13 M 43 112.6 8 1.81 1.44 3.77 225 276 0.82 14
M 18 73 5 1.24 398 402 0.56 15 M 46 84 11 1.22 441 410 0.55 16 M 42
75 7 1.87 0.60 1.62 260 268 0.84 17 M 34 122 9 1.54 0.37 0.82 332
324 0.69 18 M 42 70 8 1.77 303 283 0.80 19 M 65 100 4 0.76 800 662
0.34 20 M 33 75 12 2.41 178 207 1.09 21 M 42 80 7 1.71 335 292 0.77
Mean .+-. 38 81.5.sup.# 7* 1.66 1.60 3.76 347 344 0.75 SD 16 16.2
4-12** 0.67 0.95 2.14 148 125 0.30 *Median; **Range; .sup.#p <
0.003 between males and females.
Discussion
[0089] Clinicians have long sought an effective neuroprotective
agent to give to patients shortly following a traumatic brain
injury. The pathophysiology of brain injury is well understood, but
researchers have not identified a drug that can reliably modulate
the pathophysiologic cascade of deleterious effects that lead to
cellular necrosis, cerebral edema, and consequently, rising
intracranial pressure (Chesnut, et al. (1993) Journal of
Trauma-Injury Infection & Critical Care, 34(2):216-22;
Povlishock and Jenkins (1995) Brain Pathology, 5(4):415-26). The
treatment of traumatic brain injury is predominantly supportive in
nature, and revolves around efforts to maintain cerebral perfusion
pressure and adequate oxygenation (Brain Trauma Foundation (1996)
"Guidelines for the Management of Severe Head Injury," Journal of
Neurotrauma, 13(11):643-5; Brain Trauma Foundation B (2000)
"Management and Prognosis of Severe Traumatic Brain Injury, Parts I
& II," Journal of Neurotrauma, 17(June/July):449-627).
[0090] A substantial and rapidly growing body of data indicates
that the hormone progesterone, a neurosteroid that is naturally
found in the brains of men and women, has potent neuroprotective
properties. The data presented herein obtained during the first
pilot, randomized controlled clinical trial of progesterone for
treatment of moderate to severe acute traumatic brain injury (TBI).
In addition to testing whether the drug is safe and efficacious for
this condition, we sought to determine the pharmacokinetic
properties of intravenous progesterone in multi-system trauma
patients.
[0091] The major findings of our investigation are: 1) A solution
of progesterone in 95% ethyl alcohol is stable for up to 2 years at
room temperature; 2) Intralipid.RTM. solutions containing
progesterone in 95% ethyl alcohol are stable for a minimum of 24
hours; 3) A C.sub.SS of progesterone can be rapidly achieved and
maintained in acute, critically ill traumatic brain injured
patients with multi-system trauma using a two phase intravenous
infusion paradigm; 4) Progesterone C.sub.SS values can be
accurately predicted from AUC data; 5) The hyperkinetic physiologic
alterations accompanying acute traumatic brain injury result in
significant elevations in CL, t.sub.1/2, and V.sub.d for
progesterone; 6) Acute traumatic brain injury, per se, does not
result in endogenous release of progesterone; and 7) Alterations in
progesterone pharmacokinetics following acute traumatic brain
injury are not gender dependent. One of the most important goals in
clinical pharmacokinetics is obtaining patient specific estimates
of the appropriate pharmacokinetic parameters. The use of model
independent methods (AUC) is extremely robust for determining
patient specific CL. CL is the primary parameter of interest when
drugs are being administered by continuous intravenous infusion,
since the resultant patient-specific C.sub.SS is dependent only on
infusion rate and CL. The current study demonstrates that stable
C.sub.SS values of progesterone were rapidly achieved with
intravenous administration, making dosing adjustments to realize a
target concentration practical in a population of critically
injured patients regardless of gender. While the number of patients
in this investigation receiving a placebo infusion is small,
repeated sampling and analysis shows that the initial progesterone
concentrations are constant over the 84-hour time course of study.
These data suggest that endogenous secretion of progesterone is not
significantly stimulated by traumatic brain injury, per se. The
ultimate goal, of course, is to define the C.sub.SS that correlates
with optimum treatment efficacy. Once the pharmacodynamic
relationship between steady state serum concentration of
progesterone and clinical outcome is elucidated, the parameters
determined in our study may be used to draft an infusion paradigm
that optimizes the odds of survival and functional recovery. Since
the C.sub.SS are rapidly achieved and are stable, patient-specific
adjustments in infusion rate to maintain a target concentration
should be possible with minimal early blood sampling. If such a
pharmacologic intervention proves efficacious, our stability data
demonstrate that stock solutions of progesterone in ethanol, which
are tedious to prepare, can be safely used for up to two years.
This would allow neurotrauma units immediate access to progesterone
solutions and facilitate rapid treatment implementation.
[0092] In 1993, the Brain Injury Foundation convened an
international task force to develop evidence-based guidelines for
treatment of traumatic brain injury (Brain Trauma Foundation (1996)
"Guidelines for the Management of Severe Head Injury," Journal of
Neurotrauma, 13(11):643-5; Brain Trauma Foundation B (2000)
"Management and Prognosis of Severe Traumatic Brain Injury, Parts I
& II," Journal of Neurotrauma, 17(June/July):449-627; Roberts,
et al. (1998) J Neurol Neurosurg Psychiatry, 65(5):729-33). With
the exception of mannitol and barbiturates, no pharmacological
agents were identified that enhance recovery.
[0093] In the current study, additional drugs were co-administered
to optimize the medical management of these critically injured
patients. The drug combinations and dosing regimens were
individualized on a patient-specific basis. As such, there was not
a consistent group of these drugs given to all patients. While a
number of the additional drug classes, in particular, the
anticonvulsants and barbiturates can result in altered physiology
including increases in hepatic blood flow and increases in
oxidative metabolism, we cannot unequivocally determine whether the
increased values for progesterone clearance are a result of
concomitant drug administration, or traumatic brain injury.
Finally, because the drug is available in generic forms it is
inexpensive.
[0094] Using the results from this study coupled with future
findings from a dose response efficacy trial, investigators will be
able to adjust infusion rates of progesterone to achieve optimal
steady-state concentrations. If intravenous infusion of
progesterone proves to produce benefits in acutely brain-injured
humans it will represent a major advance in the treatment of this
common and devastating condition.
Example 2
[0095] A pilot phase II, randomized, double-blind, controlled trial
of progesterone for the treatment of a traumatic brain injury was
preformed. The administration protocol was carried out was
described above in Example 1.
[0096] To determine if a therapeutic response was achieved, the
following endpoints were monitored:
[0097] ICP reduction determined by calculating "therapeutic
intensity level" (ICP-TIL);
[0098] duration of coma (injury to awaking);
[0099] mortality one-month post injury;
[0100] neurological outcome 1 month and 1 year post-injury, as
determined by Glasgow outcome scale (GOS), Disability rating scale
(DRS) and Galveston orientation and amnesia test (GOAT).
[0101] The preliminary evaluations are as follows. One hundred
patients having moderate to severe TBI were enrolled in the study,
which had a randomized block design 4:1 enrollment. Three days IV
administration of progesterone [450+/-mmol/L] in both males and
females. The administration protocol and pharmaceutical composition
administered are described in detail in Example 1. Follow up
regarding condition occurred at 30 days and 1 year.
[0102] Control subjects has a 30.4% mortality rate, while subjects
having the progesterone treatment had a 12.9% mortality rate. The
progesterone treatment group also had a 60% reduction in brain
deaths. Table 3 summarizes the results.
TABLE-US-00003 TABLE 3 Death Frequency percent Treatment row Pct
Col Pct A B Total Medicinal death 5 2 7 5.05 2.02 7.07 Brain death
4 5 9 4.04 5.05 9.09 Not Dead 67 16 83 67.68 16.16 83.84 Total 76
23 99 100.00
[0103] For test of significance in Table 3, the .chi..sup.2 test
with 2 df was significant (p=0.0471). When the treatment groups
were compared with respect to the proportion of subjects
experiencing brain death (vs. those who experience medical death of
who are not dead), we find that the group A has a significantly
lower proportion than the B group (p=0.0295 by Fisher's exact
test). When the treatment groups with respect to proportion of
subjects experiencing medical death (vs. those who experience brain
death or who are not dead), it was found that the groups are not
statistically significant (p=0.6622 by Fisher's exact score).
Example 3
[0104] We conducted a clinical trial to assess the safety of
progesterone as a treatment for acute TBI. This phase II,
randomized, double blind, placebo-controlled clinical trial was
conducted at an urban, level I trauma center. 100 adults presenting
within 11 hours of a blunt TBI with a Glasgow Coma Scale score of
4-12 were enrolled with proxy consent. Subjects were randomized on
a 4:1 basis to progesterone versus placebo. Blinded observers
closely monitored patients for the occurrence of adverse events,
and initial functional outcomes were assessed 30 days post-injury.
The primary safety outcome was difference in adverse event rates,
including mortality. The primary measure of activity was
dichotomized Glasgow outcome scale extended (GOSE) 30 days post
injury. Seventy-seven patients received progesterone; 23 received
placebo. The groups had very similar demographic and clinical
characteristics. With the exception of mortality, the rate of
adverse events was similar in both groups. Laboratory values and
physiological parameters were similar as well. No serious adverse
events were attributed to progesterone. GOSE and other measures of
neurological outcome were not significantly different between
groups, but progesterone-treated subjects had a lower all-cause 30
day mortality rate than controls (rate ratio 0.43; 95% confidence
interval 0.18-0.99). In this pilot study progesterone caused no
observable harms and showed promising signs of activity for
treating TBI.
Introduction
[0105] Between 1.5 to 2 million Americans sustain a TBI each year.
In the U.S. alone, TBI is annually responsible for 50,000 deaths,
235,000 hospitalizations, and 80,000 cases of long term disability.
Approximately 37,000 of these victims experience moderate
disabilities (Thurman (2001) "The epidemiology and economics of
head trauma," in Head Trauma: Basic, Preclinical, and Clinical
Directions, ed. Miller (Wiley and Sons); Kraus (1997) "Epidemiology
of head injury," in Head Injury, ed. Cooper (2nd ed, Williams &
Wilkins Co., Baltimore); Selecki et al. (1982) Australian & New
Zealand Journal of Surgery 52(1):93-102; Klauber et al. (1981) Am J
Epidemiol 113(5):500-509; Max et al. (1991) Journal of Head Trauma
Rehabilitation 6(2):76-91; Gentleman et al. (1992) Injury
23(7):471-474; Jones et al. (1994) Journal of Neurosurgical
Anesthesiology 6(1):4-14.; Cohadon et al. (1991) Journal of the
Neurological Sciences 103 Suppl:S27-31; and, Sakata et al. (1991)
Brain Injury 4:411-419. ) and 17,000 require specialized care for
life. The CDC estimates that 5.3 million Americans are living with
disability from TBI. Lifetime costs of TBI are estimated to exceed
$56 billion per year (Thurman (2001) "The epidemiology and
economics of head trauma," in Head Trauma: Basic, Preclinical, and
Clinical Directions, ed. Miller (Wiley and Sons)). We conducted a
pilot clinical trial to assess the safety and potential efficacy of
administering intravenous progesterone to victims of moderate to
severe acute traumatic brain injury.
Methods
[0106] Study Design: The primary objective of this phase II
randomized, double blind, placebo-controlled trial was to assess
potential harms of administering intravenous progesterone to
acutely brain-injured patients of both sexes. We also hoped to
detect signals of activity.
[0107] In the US, IV progesterone had been authorized for
experimental use in only three previous clinical studies, none of
which were related to TBI (Aebi et al. (1999) Cancer Chemotherapy
& Pharmacology 44(3):259-265; Allolio et al. (1995) European
Journal of Endocrinology 133(6):696-700; and, Christen et al.
(1993) Journal of Clinical Oncology 11(12):2417-2426). The present
study shows that IV administration of progesterone following TBI
would not result in an increased rate of adverse or serious adverse
events.
[0108] According to the U.S. Food and Drug Administration, an
"adverse event" is any undesirable medical event occurring to a
subject in a clinical trial, whether or not related to the study
drug. This includes events not seen at baseline, or worsened if
present at baseline. "Serious adverse events" are defined as death,
immediate risk of death, or suspicion that use or continued use
would result in the patient's death, prolongation of existing
hospitalization, persistent or significant disability/incapacity,
or a congenital anomaly/birth defect.
[0109] To detect adverse events, blinded observers screened each
study subject on a daily basis to identify a wide range of adverse
events, including but not limited to those that that could be
plausibly related to progesterone administration. These included
any thromboembolic event (deep vein thrombosis, thrombophlebitis,
ischemic myocardial infarction, pulmonary embolism, stroke or
transient ischemic attack), elevated liver enzymes, temperature
elevation, allergic reactions, and hyperglycemia. All laboratory
test results obtained during the course of treatment were recorded
and analyzed to detect abnormal levels or worrisome trends. An
independent internal safety monitor made the determination if an
adverse event was associated with study treatment. Both the FDA and
an independent NIH-appointed data safety monitoring board
independently reviewed these determinations.
[0110] In addition to monitoring subjects for signs of harm, we
hoped to detect signals of activity. We hypothesized that treatment
with progesterone might reduce 30 day mortality and improve a
number of short term outcomes following TBI. For this preliminary
study, our primary outcome of interest was Glasgow Outcome Scale
Extended (GOSE) 30 days post-injury. Other outcome measures at 30
days included group mortality, Disability Rating Scale score,
duration of coma, duration of post-traumatic amnesia, and control
of increased intracranial pressure.
[0111] Setting: The study was conducted at an urban public hospital
with over 100,000 patients visits per year, the regions only level
I trauma center serving a metropolitan population of more than 4
million.
[0112] Selection of participants: Consecutive adult victims of
blunt TBI who reached Grady within 11 hours of injury with a
post-stabilization or "index" Glasgow Coma Scale score (iGCS) of
4-12 were eligible for enrollment (FIG. 5). Only 3 potentially
eligible patients were missed during the 2.5-year enrollment period
(May 28, 2002 and Sep. 17, 2004).
[0113] Whenever a potential candidate was identified, a study
investigator came to the emergency department within 30 minutes to
assess eligibility. Exclusion criteria included a blood alcohol
concentration of >250 mg/dl; penetrating brain injury; age
<18 years; an iGCS of <4 or >12; indeterminate time of
injury; pregnancy; cancer; stroke; spinal cord injury; or unable to
secure proxy consent within 11 hours of injury.
[0114] Because patients could not consent for themselves, a legally
authorized representative was approached. Proxies were informed of
the study's rationale, design, and anticipated benefits and risks.
They were assured that participation was voluntary, and
nonparticipation would not affect the patient's care. To facilitate
comprehension, our consent form was drafted at an 8.sup.th grade
reading level. A Spanish language version was produced as well. An
investigation new drug authorization to use intravenous
progesterone to treat TBI was obtained from the U.S. Food and Drug
Administration, and a NIH-appointed DSMB provided independent
guidance and oversight. The hospital's Research Oversight Committee
and the University's Institutional Review Board approved our study.
Before initiating enrollment, we briefed leaders of several local
advocacy organizations. We also convened a community advisory
board.
[0115] Interventions: Following proxy consent, patients were placed
in one of 8 clinical subgroups defined by gender (male versus
female), race (black versus all others) and TBI severity (moderate
versus severe). Within each subgroup, permuted block randomization
was employed to assign 4 out of every 5 consecutive patients to
progesterone and the other to placebo (4:1 randomization). This
asymmetric approach was adopted at the request of our NIH-appointed
DSMB to maximize the number of patients receiving study drug while
maintaining blinding.
[0116] To insure blinding of all personnel at the hospital,
including the hospital pharmacists mixing study infusions, drug
kits were prepared off-site by an Investigational Drug Center.
Vials of the study drug and placebo were identical in appearance
and physical properties. To produce a set of vials, progesterone
was dissolved in 95 percent ethanol and filtered into sterile vials
using a 0.2.mu. filter. Aliquots were assayed to confirm uniform
concentration and sterility. Each study kit contained either 6
vials of progesterone in ethanol (treatment) or 6 vials of ethanol
alone (placebo).
[0117] Whenever a patient was enrolled, the next kit in sequence
for that subgroup was used to prepare infusions. The first vial was
mixed in Intralipid.TM. 20% to deliver a one-hour loading dose of
0.71 mg/kg of progesterone at a standard rate of 14 mls/hour,
followed by a maintenance infusion of 0.5 mg/kg/h at a standard
rate of 10 mls/hour. The remaining vials were used to prepare 5
subsequent 12-hour infusions at the same standard rate of 10
mls/hour for a total of 3 days of treatment. Details of drug
monitoring are reported elsewhere (Wright et al. (2005) J Clin
Pharmacol 45(6):640-648).
[0118] Clinical services treating brain injured patients at our
hospital follow a consensus protocol based on the guidelines of the
Brain Trauma Foundation (Brain Trauma Foundation B (2000) Journal
of Neurotrauma 17(June/July):449-627). This protocol governs the
treatment of TBI patients from pre-hospital settings to hospital
discharge. A rigorous, stepwise approach is specified to treat
episodes of increased intracranial pressure (ICP). Adopting this
protocol assured that with the exception of treatment group
assignment, all study participants received standard treatment for
TBI.
[0119] Methods of Measurement: To assess drug safety, study
personnel rounded daily to document the occurrence of adverse
events (AEs) or serious adverse events (SAEs). Hourly vital signs
(blood pressure, heart rate, respiratory rate, temperature, and
pulse oximetry), intracranial pressure readings, and other
parameters (mean arterial pressure, cerebral perfusion pressure,
and fluid balance), were abstracted from each patient's chart.
Laboratory values were obtained from the hospital's information
system, and concomitant medications and interventions were
noted.
[0120] Whenever an SAE occurred, an independent board-certified
neurosurgeon assessed its potential relationship to study treatment
using pre-defined scale. SABs were reported within 24 hours to the
Institutional Review Board (IRB), our NIH-appointed Data Safety
Monitoring Board (DSMB), and the U.S. Food and Drug Administration.
All other adverse events were reported to on a weekly basis.
[0121] The infusion was stopped if a patient experienced an
anaphylactic reaction, a major thromboembolic event, an unexplained
elevation of serum aspartate aminotransferase (AST) or alanine
aminotransferase (ALT) to a level greater than 5,000 IU, or a serum
total bilirubin level greater than 10 mg/dl. We agreed to
prematurely halt enrollment if either of 2 interim analyses
revealed that one group or the other experienced a significantly
higher rate of SAEs, including mortality, than the other. These
rules were based on O'Brien-Fleming boundaries (O'Brien and Fleming
(1979) Biometrics 35(3):549-556), constructed using an alpha
spending approach (DeMets and Lan (1994) Statistics in Medicine
13(13-14):1341-1352; discussion 1353-1346).
[0122] To determine if the study drug had a beneficial impact on
patients, we collected a variety of physiological and functional
measures. These included: hourly intracranial pressure
measurements; duration of coma, defined as the number of hours from
injury to awakening (GCS>8 or motor score >5), and duration
of post-traumatic amnesia, defined as the number of days until a
subject achieved two consecutive Galveston Amnesia and Orientation
test scores of 75 or better. Thirty days following each injury
event, we assessed each patient's Glasgow Outcome Score Extended
(GOSE) and Disability Rating Scale (DRS). Patients who were
severely impaired were classified as "not testable"--a surrogate
marker for a poor outcome. Reliability codes were used to record
reasons for non-administration of a particular measure, such as
physical impairment (e.g., hemiparesis) cognitive impairment (e.g.,
could not understand instructions), or intoxication. One-year
outcomes will be reported at a later date.
[0123] Data collection and processing: Data collection was guided
by a formal data management plan and standard operating procedures
manual. Data collected at the bedside were recorded on paper case
report forms (CRFs) and subsequently double entered into a
web-based ORACLE.RTM. database. Entered CRFs were not accepted as
valid unless the double entries matched and all range checks were
met. Special edit queries were constructed to generate transport
files for importing into SAS.RTM. for analysis.
[0124] Outcome Measures: The primary aim of our study was to assess
the safety of treatment with progesterone. We hypothesized that
treatment and control groups would experience similar rates of
SAE's and AE's. Our secondary aim was to look for signs of drug
activity by assessing several measures of outcome. Our a priori
primary measure of outcome was the Glasgow Outcome Scale-Extended
(GOSE) (Teasdale et al. (1998) Journal of Neurotrauma
15(8):587-597). Other outcome measures included: 1) death within 30
days of injury 2) duration of coma (Levin (1995) Journal of
Neurotrauma 12(5):913-922); 3) duration of post-traumatic amnesia
(Levin et al. (1979) Journal of Nervous & Mental Disease
167(11):675-684); 4) mean intracranial pressure and intracranial
pressure therapeutic intensity level (ICP-TIL) (Maset et al. (1987)
Journal of Neurosurgery 67(6):832-840) and 5) the Disability Rating
Scale (DRS) (Hall et al. (2001) Arch Phys Med Rehabil
82(3):367-374).
[0125] Primary Data Analysis--Treatment and placebo groups were
compared with respect to a variety of demographic, historical and
prehospital characteristics to ensure that important independent
predictors of outcome were equally distributed. Next, the groups
were compared with respect to rates of adverse and serious adverse
events, using Fisher's exact test. Generalized linear model
analysis using a negative binomial distribution was used to compare
rates of events that occurred multiple times per patient within the
first 30 days (McCullagh and Nelder (1989) Generalized Linear
Models (2nd ed, Chapman & Hill)). Then, group specific
differences in 30-day outcomes. Fisher's exact test was used to
analyze GOSE scores dichotomized into "good or moderate recovery"
versus all other levels. Wilcoxon's rank sum test was used to
compare group specific DRS scores. Mean and median durations of
coma and post-traumatic amnesia were compared using student's
t-test. All analyses were stratified on an a priori basis by brain
injury severity (iGCS 4-8 (severe) versus iGCS 9-12 (moderate)).
Longitudinal mixed effects models were used to analyze ICP-TIL as
well as other hourly or daily clinical measurements from enrollment
through treatment day 4.
[0126] To insure that any observed differences in mortality were
associated with the study treatment rather than confounding
clinical factors, additional multivariate analyses were performed.
Variables determined to be independently associated with all-cause
mortality or CNS related-death, such as iGCS (dichotomized into
moderate versus severe), injury severity score and Marshall CT
score were incorporated in a stepwise logistic regression analyses.
Because GCS often fluctuates during the first few hours after
injury, additional stepwise logistic regressions were performed
using dichotomized GCS 1 day post-injury.
Results
[0127] Screening and Enrollment--A total of 281 patients were
screened. Three potentially eligible patients were missed and 18
patients could not be enrolled because their identity was unknown
or a proxy could not be contacted within 11 hours of injury. Six
potentially eligible patients who presented during one of 3
procedural "holds" could not be enrolled. One patient was excluded
after consent but prior to randomization because the treating team
decided that his injuries were non-survivable. Eleven eligible
patients were not enrolled because their proxy declined to consent.
(FIG. 1) Non-participants resembled participants with respect to
gender, race, and mechanism of injury.
[0128] Characteristics of study subjects--Seventy-one patients were
male; 34 were black. Mean age was 36 years. Seventy-two patients
(72%) had an iGCS of 4-8; the remainder had a score of 9-12. More
than 80% of injuries were caused by a motor vehicle crash or a
fall. Most patients reached the hospital within an hour of injury;
58 percent by helicopter. Because it frequently took several hours
to locate a representative for proxy consent, mean time from injury
to initiation of study infusion was 6.3 (95% CI 5.9-6.8) hours in
the progesterone group and 6.2 (95% CI 5.9-6.6) hours in the
placebo group.
[0129] Randomization--77 subjects were randomized to progesterone;
23 to placebo. Treatment groups were highly similar with respect to
gender, age, race, IGCS, mechanism of injury, revised trauma score,
injury severity score, time from injury to E.D. arrival, time to
study treatment, Marshal CT score (Marshall et al. (1991) J
Neurosurgery 75 (suppl):S14-20), and E.D. disposition (Table
4).
[0130] Dosing and protocol compliance--Our pharmacokinetic findings
are reported elsewhere (Wright et al. (2005) J Clin Pharmacol
45(6):640-648). One patient randomized to progesterone died before
the study drug could be initiated. She was retained in our analysis
under the principle of "intention to treat." All other members of
the treatment group and no members of the control group had high
serum levels of progesterone in their sera during drug
administration. Minor protocol violations, such as brief delays in
changing I.V. bags, were common. Sufficient solution was provided
to prevent these from interrupting infusion.
[0131] Six major protocol violations occurred. Four involved
prolonged interruptions of the infusion, one involved a dosing
error, and one involved inappropriate enrollment of a motor vehicle
crash victim. When a repeat CT scan on the second hospital day
revealed an ischemic stroke, his progesterone infusion was promptly
stopped. Subsequent review of the admission CT scan showed subtle
but clear signs of the stroke, which was traced to a traumatic
carotid artery dissection. Because the stroke predated treatment,
this incident was classified as a major protocol violation rather
than a SAE.
[0132] Safety--Aggregate and individual rates of adverse and
serious adverse events were not different between groups (Table 5).
This was true whether AEs and SAEs were analyzed by any occurrence
or by mean episodes per subject. Laboratory values of the treatment
groups were remarkably similar, whether analyzed by group means or
the frequency with which a specified test value exceeded
pre-specified thresholds. Progesterone-treated subjects experienced
a significantly lower rise in mean temperature over the infusion
interval compared to controls. This was determined by analyzing a
treatment by time interaction term for progesterone versus control
patients, with the slope=-0.0055 (95% CI, -0.010 to -0.001).
[0133] The only adverse events specifically ascribed to
administration of progesterone were two cases of superficial
phlebitis at the IV site. Both resolved spontaneously. Three
patients, all of whom received progesterone, developed a deep vein
thrombosis between 6 to 23 days following completion of the
infusion. All 3 cases were treated without incident. Two patients
suffered ischemic strokes. One in a patient randomized to
progesterone, occurred prior to treatment and was considered a
major protocol violation. The other involved a patient randomized
to placebo. A patient randomized to progesterone sustained a
myocardial infarction two days after the study infusion was
completed. At the time, he was receiving high-dose neosynephrine in
an effort to boost his cerebral perfusion pressure. Post-mortem
revealed no intra-coronary thrombosis.
[0134] Signals of benefit--During the first 4 days post-injury,
mean intracranial pressure levels (ICPs) of progesterone-treated
subjects with monitors in place remained stable, while mean ICPs
among placebo-treated subjects with ICP monitors in place tended to
rise. However, these trends were not statistically significant.
Mean ICP-TIL scores did not significantly differ between groups
(Table 6).
[0135] Severe TBI patients (IGCS 4-8) treated with progesterone
remained in coma significantly longer than survivors who received
placebo (mean duration 10.1 days (7.7, 12.5) versus 3.9 days (2.5,
5.4) respectively). The mean duration of posttraumatic amnesia did
not significantly differ between groups (Table 7). Ten of 77
patients (13 percent) randomized to progesterone died within 30
days of injury, compared to 7 of 23 patients (30.4 percent)
randomized to placebo (rate ratio 0.43, 95% CI 0.18-0.99). When the
analysis was restricted to the 99 subjects who received treatment,
this difference was more significant (rate ratio 0.39, 95%
confidence interval 0.16, 0.93). Deaths due to neurological causes
tended to be lower in the treatment group than controls (rate ratio
0.30, 95% confidence interval 0.08-1.12) while deaths from non CNS
causes did not appreciably differ. The association between
treatment group and mortality remained robust in multivariate
models, including several based on dichotomized GCS at 24 hours
(Table 7).
[0136] We were able to contact 92 percent of survivors 30 days
post-injury to assess their functional status. Our primary outcome
measure, dichotomized GOSE, did not significantly differ between
groups. The DRS scores of severely brain injured patients were
similar as well. However, moderately brain-injured patients
randomized to the study drug achieved significantly better DRS
scores, on average, than those randomized to placebo (Table 7).
Discussion
[0137] Because progesterone has not been previously used to treat
acute traumatic brain injury, we conducted a pilot, phase II study
to assess potential harms. Arriving patients were carefully
screened for eligibility. Ninety nine percent of potentially
eligible patients were screened, and 90 percent of those who met
inclusion criteria were enrolled with proxy consent. Treatment and
control patients were well matched by injury severity, time to
treatment and other independent predictors of outcome.
[0138] The decision to secure proxy consent rather than seek
exemption from informed consent delayed initiation of treatment an
average of 6.5 hours. Although one animal study has suggested that
progesterone may produce beneficial effects as late as 24 hours
post-injury, the magnitude of benefit was greatest when treatment
was administered within 2 hours of injury (Roof et al. (1996) Exp
Neurol 138(2):246-251).
[0139] Three members of the treatment group developed deep vein
thrombosis--the earliest 6 days post-infusion. This frequency is
well within our institution's historical incidence of DVT in major
trauma patients (unpublished data). With the exception of
mortality, treatment and control groups experienced similar rates
of AEs and SAEs. They also had very similar lab and physiological
values.
[0140] Our secondary goal was to detect signs of drug activity. We
chose GOSE as our primary outcome measure because it the most
widely used standard in the brain injury literature. We observed
promising signs of activity.
[0141] No differences were found in mean ICP or mean ICP-TILs.
[0142] There was no significant difference between treatment groups
with respect to duration of post-traumatic amnesia and 30-day GOSE.
However, the 30-day mortality rate among subjects randomized to the
treatment group was less than half that of the control group. This
difference persisted after other important predictors of outcome
were taken into consideration.
[0143] Severely brain-injured patients in the treatment group had a
longer mean duration of coma than those in the control group. This
may represent a "survivor effect". If progesterone prevented the
deaths of several patients during the 30 day follow up period, it
is not surprising that these survivors remained in coma for a
longer duration of time. One-year survival and functional outcomes
will be reported at a later date.
[0144] In retrospect, we would have preferred to enroll patients
with exception to informed consent. This would have allowed us to
start the study treatment much sooner, and enroll patients who were
lost because we could not find a legally authorized representative
within the enrollment window. Earlier administration of the study
drug might have produced greater evidence of activity. We
recognized, however, that this is the first human trial of
progesterone in the setting of acute brain injury and our study was
primarily designed to assess drug safety rather than activity. This
is why we enrolled patients with proxy consent and accepted
potentially significant treatment delays (up to 11 hours) to
maximize recruitment. Based on our encouraging findings with
regards to safety, we hope to conduct a larger trial under the
federal regulatory framework that allows exception from consent in
limited circumstances (Federal regulations of 21CFR50.24). This
will enable earlier initiation of treatment and maximize the
opportunity to detect any evidence of neuroprotective effects.
[0145] In summary, this study represents an important step in
assessing the utility of progesterone for treating acute traumatic
brain injury. TBI is a leading cause of death and disability
worldwide. No pharmacological agent has been shown to improve
outcomes. We previously reported that progesterone can be
accurately administered in intravenous form to victims of TBI
(Wright et al. (2005) J Clin Pharmacol 45(6):640-648). This
analysis offers preliminary evidence that this treatment causes no
harm and may have disease-modifying activity. A clinical trial
involving more subjects, 1:1 randomization, and a short enrollment
window is warranted. If it corroborates our findings, this will
represent a major advance in brain injury care.
TABLE-US-00004 TABLE 4 Characteristics by Group: Participants in
ProTECT .TM. (N = 100) Characteristic Overall Progesterone Placebo
p-value* Number of Subjects 100 77 23 N/A Mean Age (X .+-. sd) 35.8
.+-. 15.0 35.3 .+-. 14.3 37.4 .+-. 17.4 0.54 Male (%) 71% 71% 70%
0.86 African American (%) 35% 34% 39% 0.64 Mechanism of Injury (%)
(n = 100) Motor Vehicle 76 74 83 0.58 Pedestrian Struck 3 4 0 (mvc
vs. all Bicycle 3 3 4 other) Fall 7 6 9 Other 11 13 4 Index GCS (%
severe) 72% 73% 70% 0.77 24 hr GCS (% severe) 61% 70% 50% 0.23
Injury Severity Score (X .+-. sd) 24.2 .+-. 9.2 24.5 .+-. 9.9 23.3
.+-. 6.4 0.50 Revised Trauma Score (X .+-. sd) 6.1 .+-. 0.6 6.1
.+-. 0.6 6.2 .+-. 0.7 0.83 Probability of Survival (P .+-. sd) 0.9
.+-. 0.2 0.9 .+-. 0.2 0.8 .+-. 0.1 0.53 Initial CT scan Marshall
Score.sup.67 2.8 .+-. 1.6 3.0 .+-. 0.2 2.3 .+-. 0.3 0.09 (1-5) Time
injury to arrival (X .+-. sd) 50.3 .+-. 30.3 49.5 .+-. 32.3 54.3
.+-. 32.3 0.42 min Time injury to infusion (X .+-. sd) 379.2 .+-.
118.0 380.7 .+-. 125.6 374.0 .+-. 91.2 0.78 min *p value =
progesterone group versus placebo group
TABLE-US-00005 TABLE 5 30-Day Adverse Event Rates by Treatment
Group Progesterone Placebo Relative Risk (95% (%) (%) confidence
interval) Acute respiratory distress 2.6 4.4 0.60 (0.06, 6.29)
syndrome Central nervous system 1.3 0.0 -- infection Cardiac
Arrhythmia 5.2 17.4 0.30 (0.08, 1.10) Cholestatic Jaundice 6.5 0.0
-- Death within 30 days 13.0 30.4 0.43 (0.18, 0.99) Fever 70.1 82.6
0.85 (0.67, 1.08) Gastrointestinal Bleed 5.2 0.0 --
Hyperglycemia-non DM 27.3 30.4 0.90 (0.44, 1.84) Hypertension 11.7
8.7 1.34 (0.31, 5.79) Hypotension 9.1 21.7 0.42 (0.15, 1.19)
Hypothermia 5.2 8.7 0.60 (0.12, 3.06) Hypoxemia 11.7 13.0 0.90
(0.26, 3.04) Increase Liver Enzyme 6.5 4.4 1.49 (0.18, 12.15)
Phlebitis at Injection Site 1.3 0.0 -- Rash or Hives 2.6 0.0 --
Syndrome of inappropriate 1.3 0.0 -- ADH Seizures 5.2 0.0 -- Sepsis
2.6 0.0 -- Shock 2.6 0.0 -- Suspected Pneumonia 11.7 4.4 2.69
(0.46, 20.12) Tachycardia 24.7 13.0 1.89 (0.61, 5.83)
Thromboembolic Disease 3.9 0.0 --
TABLE-US-00006 TABLE 6 Physiological Parameters Infusion Day
Progesterone Group Placebo Group DAY n mean 95% CI n mean 95% CI
Intracranial Pressure Therapeutic Intensity Level 0 16 2.6 1.9, 3.4
5 3.8 1.9, 5.7 1 27 2.7 1.4, 4.1 9 2.7 1.3, 4.1 2 26 3.2 1.9, 4.5
10 4.5 1.2, 7.8 3 17 3.7 1.1, 6.3 9 4.2 0.6, 7.9 4 15 2.8 0.6, 5.0
5 6.0 0, 12.3 Intracranial Pressure (mm Hg) 0 17 16.0 12.3, 19.7 5
13.13 8.1, 18.2 1 36 17.1 12.6, 21.5 12 14.69 10.1, 19.3 2 34 15.4
13.2, 17.5 12 17.32 12.1, 22.6 3 34 16.0 13.8, 18.2 12 18.27 13.3,
23.2 4 25 17.7 14.8, 20.7 12 19.95 13.8, 26.1 Cerebral Perfusion
Pressure (mmHg) 0 13 70.3 61.9, 78.8 3 71.9 48.4, 95.4 1 36 73.4
66.2, 80.6 12 76.8 71.5, 82.0 2 34 75.9 71.7, 80.1 12 74.9 70.6,
79.1 3 34 74.9 70.7, 79.2 12 75.6 70.8, 80.4 4 25 73.8 68.0, 79.6
11 73.2 67.2, 79.1 Systolic Blood Pressure (mmHg) 0 68 129.4 125.6,
133.2 18 127.6 119.2, 136.0 1 76 130.2 126.5, 133.9 22 129.9 124.0,
135.7 2 75 133.5 130.2, 136.8 23 133.0 125.9, 140.1 3 75 133.8
130.1, 137.6 22 137.0 130.6, 143.9 4 73 132.7 128.6, 136.9 21 137.8
132.5, 143.4 Diastolic Blood Pressure (mmHg) 0 68 69.5 66.6, 72.5
18 66.6 60.3, 72.9 1 76 67.4 65.1, 69.8 22 66.4 62.6, 70.1 2 75
67.2 64.8, 69.7 23 65.7 60.7, 70.8 3 75 67.5 65.3, 69.6 22 66.4
62.2, 70.6 4 73 67.3 65.2, 69.4 21 67.3 63.6, 71.1 Temperature
(degrees centigrade) 0 35 37.0 36.6, 37.4 11 36.9 36.3, 37.6 1 76
37.4 37.3, 37.6 22 37.4 37.1, 37.7 2 75 37.4 37.3, 37.6 23 37.7
37.4, 38.0 3 75 37.4 37.3, 37.5 22 37.7 37.4, 37.9 4 73 37.5 37.3,
37.6 21 37.7 37.4, 38.0 Fluid Balance (+mls) 1 76 767.9 312.8,
1223.0 23 834.7 0, 1794.9 2 76 1189.5 645.9, 1733.0 23 1282.2
583.4, 1981.0 3 75 802.0 401.5, 1202.5 22 1292.6 748.1, 1837.0 4 75
818.7 386.3, 1251.2 20 812.0 66.9, 1557.2 Parameters Exceeding
Threshold Values Percent of Patients with Clinical Values Exceeding
the Threshold Progesterone Group Placebo Group n denominator % # n
% p-value MAP < 70 22 76 29.0 10 23 43.5 0.21 CPP < 60 18 37
48.7 5 12 41.7 0.75 ICP > 25 12 37 32.4 5 12 41.7 0.73 Systolic
BP < 90 22 76 29.0 10 23 43.5 0.21 Mean Duration of Pressures
Exceeding Threshold Values (hours) Progesterone Group Placebo Group
Duration (hrs) n mean std error n mean std error Wilcoxon MAP <
70 76 2.5 0.7 23 3.4 1.40 0.24 CPP < 60 37 6.9 2.9 12 2.4 1.18
0.56 ICP > 25 37 5.0 2.5 12 11.3 7.88 0.46 Systolic BP < 90
76 2.7 0.7 23 3.5 1.40 0.25 Mean Frequency of Pressures Exceeding
Threshold Values Progesterone Group Placebo Group # Rate/1000 #
Rate/1000 Consecutive consecutive Consecutive consecutive p- Event
Occurrence Readings readings Occurrence Readings readings value MAP
< 128 4334 29.5 0 1477 41.3 0.81 70 CPP < 183 1969 92.9 23
816 28.2 0.41 60 ICP > 145 2067 70.2 121 828 146.1 0.61 25
Systolic 132 4112 32.1 62 1365 45.4 0.81 BP < 90 MAP = mean
arterial pressure, CPP = cerebral perfusion pressure, ICP =
intracranial pressure, BP = blood pressure
TABLE-US-00007 TABLE 7 Outcomes Variables 30 days Post Injury
Progesterone Group Placebo Group Total N 77 23 Mortality 95% Risk
Rate Confidence n % n % Ratio Interval All cause mortality (ITT)*
10 13.0 7 30.4 0.43 0.18, 0.99 All cause mortality (TR)# 9 11.8 7
30.4 0.39 0.16, 0.93 Neurological deaths# 4 5.3 4 17.4
Non-neurological deaths# 5 6.6 3 13.0 Survived > 30 days# 67
88.2 16 69.6 Total and Dichotomized Glasgow Outcome Score -
Extended 95% Risk Rate Confidence Disability level n % % n % %
Ratio Interval Dead 10 14.2 7 31.8 Vegetative State 5 7.1 0 0 Lower
Severe 28 40.0 70.0 7 31.8 81.8 Upper Severe 6 8.6 4 18.2 Lower
Moderate 8 11.4 4 18.2 1.65 0.63, 4.29 Upper Moderate 7 10.0 30.0 0
0 18.2 Lower Good 3 4.3 0 0 Upper Good 3 4.3 0 0 95% 95% Confidence
Confidence n Mean Interval n Mean Interval Disability Rating Score
Index GCS = 4-8 Employ 46 2.7 2.4, 2.9 9 2.4 1.9, 3.0 Function 46
2.9 2.3, 3.5 9 1.8 0.7, 2.8 Total DRS 45 10.7 8.0, 13.4 9 4.4 2.8,
6.1 Index GCS = 9-12 Employ 15 1.8 1.1, 2.5 6 3 -- Function 15 1.5
0.5, 2.6 6 3.8 2.6, 5.1 Total DRS 15 5 1.6, 8.4 6 12.7 7.0, 18.4
Duration of Coma (days) Initial GCS = 4-8 55 10.11 7.7, 12.5 16 3.9
2.5, 5.4 Initial GCS = 9-12 20 4.1 1.4, 6.8 7 6.1 0, 13.2 Duration
of Post-Traumatic Amnesia (days) Initial GCS = 4-8 37 18.6 15.2,
22.0 9 12.8 5.2, 20.4 Initial GCS = 9-12 15 10.7 6.2, 15.3 3 18.3
0, 46.9 *Analyses of intention to treat; #Analyses of treatment
received, one patient died prior to receiving study drug
[0146] All publications and patent applications mentioned in the
specification are indicative of the level of those skilled in the
art to which this invention pertains. All publications and patent
applications are herein incorporated by reference to the same
extent as if each individual publication or patent application was
specifically and individually indicated to be incorporated by
reference.
[0147] Although the foregoing invention has been described in some
detail by way of illustration and example for purposes of clarity
of understanding, it will be obvious that certain changes and
modifications may be practiced within the scope of the appended
claims.
* * * * *