Note: Descriptions are shown in the official language in which they were submitted.
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METHOD OF TREATING PATIENTS WITH HEPATORENAL SYNDROME TYPE 1
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims the benefit of U.S. Patent
Application No.
17/340,765, filed on June 7, 2021, the entire contents of which are hereby
incorporated
by reference.
INCORPORATION OF SEQUENCE LISTING
[0002] A computer readable text file, entitled
"105870 726724_SequenceListing_ST25.txt" created on or about 6 June 2022, with
a
file size of about 1 kilobyte contains the sequence listing for this
application and is
hereby incorporated by reference in its entirety.
TECHNICAL FIELD
[0003] Principles and embodiments of the present disclosure
relate generally
to methods of treating patients with type-1 hepatorenal syndrome.
BACKGROUND
[0004] Hepatorenal Syndrome Type-1 (HRS Type 1 or HRS-1) is
the
development of acute kidney failure in patients with late-stage liver
cirrhosis in the
absence of any other cause. It is characterized by rapid onset of renal
failure with a high
mortality rate that exceeds 80% with within three months. Renal failure is an
identified
complication of cirrhosis of the liver; and, acute renal failure is known to
have poor
prognosis for patients with cirrhosis of the liver. In various instances, the
renal failure
may be caused by hypovolemia, hepatorenal syndrome without ongoing infection,
or
hepatorenal syndrome with an ongoing infection. Unfortunately, patients with
HRS
Type-1 may die from renal failure while waiting for a liver transplant.
Currently, there is
no way of determining which patients could maximally benefit from terlipressin
treatment
to reverse HRS Type-1.
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[0005] Hepatorenal Syndrome (HRS) is indicated by low
glomerular filtration
rate due to renal vasoconstriction, splanchnic and peripheral arterial
vasodilatation
producing decreased vascular resistance, and portal hypertension. HRS is
indicated by
cirrhosis with ascites, serum levels of creatinine>133 pmo1/1 (1.5 mg/dL), no
improvement of serum levels of creatinine (decrease to a level of 133 pmo1/1)
after at
least 2 days of diuretic withdrawal and volume expansion with albumin, and the
absence of shock and parenchymal kidney disease. HRS Type 1 is indicated by
doubling of the initial serum levels of creatinine to >226 pmo1/1 (2.56 mg/dL)
in <2
weeks.
[0006] Normal creatinine levels range from 0.7 to 1.3 mg/dL in
men and 0.6 to
1.1 mg/dL in women. One mg/dlof creatinine equals 88.4 pmo1/1.
[0007] Certain mechanisms that work to maintain effective
arterial blood
volume and relatively normal arterial pressure in patients with cirrhosis,
however, affect
kidney function, such as sodium and solute-free water retention, which can
lead to
ascites and edema, and to renal failure by causing intrarenal vasoconstriction
and
hypoperfusion. Ascites can result from the combination of portal hypertension
and
splanchnic arterial vasodilation that alters intestinal capillary pressure and
permeability,
which facilitates the accumulation of the retained fluid in the abdominal
cavity.
[0008] A factor contributing to ascites formation is a
splanchnic vasodilation
that results in a decreased effective arterial blood volume. Portal
hypertension also
results from increased hepatic resistance to portal blood flow in cirrhotic
livers, and may
induce splanchnic vasodilation. There may be a marked impairment in solute-
free renal
water excretion and renal vasoconstriction, which leads to HRS.
[0009] In various instances, there may be signs of hepatic
decompensation
including INR>1.5, ascites, and encephalopathy. Hyponatremia is also a
frequent
complication of patients with cirrhosis and ascites that is associated with
increased
morbidity.
[0010] Systemic Inflammatory Response Syndrome (SIRS) is an
inflammatory
response that is not necessarily related to an infection, but may be due to
nonspecific
insults that initially produces local cytokines. SIRS is typically
characterized by four
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criteria, including (1) core body temperature of less than 36 C. (96.8 F.)
or greater
than 38 C. (100.4 F.), (2) a heart rate of greater than 90 beats per minute,
(3)
tachypnea (high respiratory rate), with greater than 20 breaths per minute;
or, an arterial
partial pressure of carbon dioxide (CO2) of less than 4.3 kPa (32 mmHg), and
(4) a
white blood cell count less than 4000 cells/mm3(4x109 cells/L) or greater than
12,000
cells/mm3(12x109 cells/L); or the presence of greater than 10% immature
neutrophils
(band forms) band forms greater than 3% is called bandemia or a "left-shift."
SIRS can
be diagnosed when two or more of these criteria are present.
[0011] Sepsis has been defined as a systemic inflammatory
response to
infection, and septic shock is sepsis complicated by either hypotension that
is refractory
to fluid resuscitation or by hyperlactatemia.
[0012] The mortality of patients suffering from HRS and SIRS
can be quite
high, approaching 70%.
[0013] A number of studies have been conducted on patients
having end-
stage liver disease and systemic inflammatory responses. One such study
described by
Thabut et al., disclosed in HEPATOLOGY, Vol. 46, No. 6, 2007 entitled "Model
for End-
Stage Liver Disease Score and Systemic Inflammatory Response Are Major
Prognostic
Factors in Patients with Cirrhosis and Acute Functional Renal Failure", which
is
incorporated herein by reference in its entirety, concluded that the presence
of SIRS
criteria with or without infection was a major independent prognostic factor
in patients
with cirrhosis and acute functional renal failure.
[0014] The presence of HRS and SIRS typically indicates a
short life span if
not effectively treated with the proper medication within a short span of
time. It is
therefore paramount that the most effective treatments for patients presenting
with
particular symptoms be identified and the patients started on an appropriate
regimen as
quickly as possible.
[0015] Terlipressin is a synthetic analogue of vasopressin
having a prolonged
effect, which acts as a peptidic vasopressin Vla receptor agonist.
Terlipressin is a
derivative of vasotocin prepared by extending the N-terminal by three amino
acid
residues, and used as a vasoactive drug in the management of hypotension.
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Terlipressin may be synthesized by coupling amino acids stepwise to one
another in a
liquid or solid phase with a peptide synthesizer. Terlipressin is a prodrug
that slowly
metabolizes to lysine-vasopressin and in this way provides prolonged
biological effect.
The half-life of terlipressin is 6 hours (the duration of action is 2-10 hr),
as opposed to
the short half-life of vasopressin, which is only 6 minutes (the duration of
action is 30-60
min).
[0016] The chemical structure for terlipressin (Gly-Lys-Pro-
Cys-Asn-Gln-Phe-
Tyr-Cys-Gly-Gly-Gly; SEQ ID NO: 1) in an injectable formulation is show below.
Gly I ____________________________
GIN,.
410
* 0 Phe
mak 410
Wis Mn
Pro
0 Lys
H2N
[0017] Molecular Formula: C52 H74 N10 015 S2
[0018] Molecular Weight: 1227.4 daltons
[0019] Appearance: Homogenous lyophilized white to off-white
solid
[0020] Solubility: Clear, colorless solution in saline
[0021] Vials: Colorless glass vials containing 11 mg of a
white to off-white
solid, 1 mg active ingredient and 10 mg mannitol.
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[0022] The active ingredient, N¨[N¨(N-glycylglycyl)glycyI]-8-L-
lysinevasopressin, is a synthetically manufactured hormonogen of 8-lysine
vasopressin,
composed of 12 amino acids and having the characteristic ring structure of a
cyclic
nonapeptide with a disulfide bridge between the fourth and the ninth amino
acid. Three
glycyl-amino acids are substituted at position 1 (cysteine) of 8-lysine-
vasopressin. By
this N-terminal extension of 8-lysine-vasopressin the metabolic degradation
rate of the
active ingredient is significantly reduced, because the glycyl molecules
inhibit rapid N-
term inal enzymatic degradation. Terlipressin may be present in pharmaceutical
compositions as a salt, diacetate salt, hydrate, and/or free base, such as
terlipressin
acetate or terlipressin diacetate pentahydrate.
SUMMARY
[0023] Principles and embodiments of the present disclosure
relate generally
to methods of treating patients having HRS-1 by administering terlipressin to
the
patients to obtain reversal of the HRS-1. In one or more embodiments, response
criteria
provide a new and useful function of indicating a likelihood of improved
response by a
patient to the administration of terlipressin.
[0024] Some aspects of the disclosure relate to a method of
treating a patient
with hepatorenal syndrome Type 1 (HRS-1) comprising: administering a dose of
terlipressin to the patient by intravenous (IV) injection, when the patient is
listed for
transplant at baseline and has a baseline model end stage liver disease (MELD)
score
of less than 35; and discontinuing administration or reducing the dose of
terlipressin in
patients with serum creatinine (SCr) 5 mg/di and/or an acute-on-chronic liver
failure
(ACLF) Grade 3. The terlipressin may be administered every 6 hours by IV bolus
injection over 2 minutes.
[0025] In some aspects, the method may further comprise
acquiring the
baseline MELD score of the patient. In additional aspects, the method may
further
comprising acquiring the SCr level in the patient prior to administering the
dose of
terlipressin to determine a baseline SCr level. In some examples, the
terlipressin may
not be administered if the baseline SCr 5 mg/di and/or the baseline ACLF grade
3.
In other aspects, the patient's risk of mortality is decreased. The patient's
place on a
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transplant list may not be compromised or impacted by the administration of
terlipressin.
In some aspects, the patient may have an increased risk of their place on a
transplant
list being compromised or impacted due to the administration of terlipressin.
In addition,
the patient's ICU stay, non-ICU stay, and/or total length of hospital stay may
be
shortened. In some aspects, terlipressin administration is continued until
there is a
complete response or a partial response. In other aspects, discontinuing
administration
or reducing the dose of terlipressin occurs in patients with respiratory
failure. The
patient may also have severe kidney disease, pulmonary edema, dyspnea, or a
combination thereof. In various aspects, the method may further comprise
monitoring
the patient's oxygen saturation during treatment with terlipressin. The
monitoring of the
oxygen saturation decreases the occurrence of adverse events.
[0026] Additional aspects of the disclosure relate to a method
of treating a
patient with hepatorenal syndrome Type 1 (HRS-1) comprising: administering a
dose of
terlipressin to the patient by intravenous (IV) injection when the patient has
a baseline
model end stage liver disease (MELD) score of less than 35 and is listed for
transplant.
The method may further comprise acquiring the baseline MELD score of the
patient. In
some aspects, the method may further comprise not administering, discontinuing
administration, or reducing the dose of terlipressin in patients with serum
creatinine
(SCr) 5 mg/d1 and/or an acute-on-chronic liver failure (ACLF) Grade 3.
[0027] Further aspects of the disclosure relate to a method of
treating a
patient with hepatorenal syndrome Type 1 (HRS-1) comprising: acquiring a
baseline
model end stage liver disease (MELD) score of the patient; acquiring a SCr
level in the
patient prior to administering a dose of terlipressin to determine a baseline
SCr level;
and administering a dose of terlipressin to the patient if the baseline MELD
score is <
35, the baseline SCr level is < 5 mg/di, the patient has an ACLF Grade < 3, or
a
combination thereof. In some aspects, the patient may be listed for
transplant. In
additional aspects, the patient may have a MELD score 35 if the patient is not
listed
for transplant at baseline. The terlipressin may be administered to the
patient by
intravenous (IV) injection.
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[0028] Yet further aspects of the disclosure relate to a
method of treating a
patient with hepatorenal syndrome Type 1 (HRS-1) comprising: administering a
dose of
terlipressin to a patient by intravenous (IV) injection, wherein
administration only occurs
if the patient is listed for transplant at baseline and has a baseline model
end stage liver
disease (MELD) score < 35, the patient has a serum creatinine (SCr) <5 mg/di,
the
patient has an ACLF Grade < 3, or a combination thereof. In some aspects, the
method
may further comprise: monitoring the patient for fluid overload during
treatment with the
terlipressin; and reducing or discontinuing the terlipressin dose if fluid
overload
develops. In addition, the method may further comprise administering diuretics
to the
patient and/or measuring the SCr level in the patient.
[0029] Other aspects of the disclosure relate to a method of
increasing overall
survival of a patient with hepatorenal syndrome Type 1 (HRS-1), the method
comprising: acquiring a baseline model end stage liver disease (MELD) score of
the
patient; acquiring a SCr level in the patient to determine a baseline SCr
level; and
administering a dose of terlipressin to the patient if the patient's baseline
MELD score is
<35 and the baseline SCr level is < 5 mg/dl. In some aspects, the patient may
be listed
for transplant at baseline. In additional aspects, the patient may have a MELD
score
35 if the patient is not listed for transplant at baseline.
[0030] Additional aspects of the disclosure relate to a method
of decreasing
an overall ICU or hospital stay of a patient with hepatorenal syndrome Type 1
(HRS-1),
the method comprising: acquiring a baseline model end stage liver disease
(MELD)
score of the patient; acquiring a SCr level in the patient to determine a
baseline SCr
level; and administering a dose of terlipressin to the patient if the
patient's baseline
MELD score is < 35 and the baseline SCr level is < 5 mg/d1. In some aspects,
the
patient may be listed for transplant at baseline. In additional aspects, the
patient may
have a MELD score 35 if the patient is not listed for transplant at baseline.
[0031] Additional aspects of the disclosure relate to a method
of increasing a
complete response of a patient with hepatorenal syndrome Type 1 (HRS-1), the
method
comprising: acquiring a baseline model end stage liver disease (MELD) score of
the
patient; acquiring a SCr level in the patient to determine a baseline SCr
level;
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administering a dose of terlipressin to a patient by intravenous (IV)
injection if the
patient's baseline MELD score is < 35 and the patient's baseline SCr level is
< 5 mg/di;
measuring the SCr level in the patient during administration of terlipressin;
and
continuing administration of terlipressin until the patient's SCr level is
mg/d1. In
some aspects, the patient may be listed for transplant at baseline. In
additional aspects,
the patient may have a MELD score 35 if the patient is not listed for
transplant at
baseline.
[0032] Further aspects of the disclosure relate to a method of
increasing a
partial response of a patient with hepatorenal syndrome Type 1 (HRS-1), the
method
comprising: acquiring a baseline model end stage liver disease (MELD) score of
the
patient; acquiring a SCr level in the patient to determine a baseline SCr
level;
administering a dose of terlipressin to a patient by intravenous (IV)
injection if the
patient's baseline MELD score is < 35 and the patient's baseline SCr level is
< 5 mg/di;
measuring the SCr level in the patient during administration of terlipressin;
and
continuing administration of terlipressin until the patient experiences
greater than 20%
improvement in serum creatinine. The administration may be continued until the
patient
experiences greater than 30% improvement in serum creatinine. In some aspects,
the
patient may be listed for transplant at baseline. In additional aspects, the
patient may
have a MELD score 35 if the patient is not listed for transplant at baseline.
[0033] Other aspects of the disclosure relate to a method of
treating a patient
with hepatorenal syndrome Type 1 (HRS-1) comprising: administering a dose of
terlipressin to the patient by intravenous (IV) injection, wherein the patient
is excluded
from treatment if the patient is listed for liver transplant with a MELD score
[0034] Further aspects of the disclosure relate to a method of
treating a
patient with hepatorenal syndrome Type 1 (HRS-1) comprising: administering a
dose of
terlipressin to the patient by intravenous (IV) injection, wherein the patient
is only
treated if the patient belongs to a patient population that has median waiting
time from
listing to transplant of 5.6 months or greater.
[0035] Yet further aspects of the disclosure relate to a
method of treating a
patient with hepatorenal syndrome Type 1 (HRS-1) comprising: administering a
dose of
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terlipressin to the patient by intravenous (IV) injection, wherein the patient
is excluded
from treatment if the patient belongs to a patient population that has median
waiting
time from listing to transplant of 0.23 months or less.
[0036] Some aspects of the disclosure relate to a method of
treating a patient
with hepatorenal syndrome Type 1 (HRS-1) comprising: narrowing the population
of
eligible patients for treatment to a mitigated population to reduce the risks
selected from
the group consisting of respiratory failure, serious adverse events, death,
and
combinations thereof; and administering a dose of terlipressin to the patient
of the
mitigated population by intravenous (IV) injection.
[0037] Additional aspects of the disclosure relate to a method
of administering
terlipressin to treat a patient with hepatorenal syndrome Type 1 (HRS-1), the
patient
being listed for transplant at a baseline model end state liver disease (MELD)
score of
less than 35, the method comprising: administering to the patient a dose of
terlipressin
by intravenous (IV) injection; and discontinuing administration or reducing
the dose of
terlipressin in patients with a serum creatinine (SCr) level 5 mg/di and/or an
acute-on-
chronic liver failure (ACLF) Grade 3. In some aspects, the method may further
comprise acquiring the SCr level in the patient prior to administering the
dose of
terlipressin to determine a baseline SCr level. The patient's risk of
mortality may be
decreased. The patient's place on a transplant list may not be compromised or
impacted. The patient's ICU stay, non-ICU stay, and/or total length of
hospital stay may
be shortened. In some aspects, terlipressin administration is continued until
there is a
complete response or a partial response. In other aspects, discontinuing
administration
or reducing the dose of terlipressin occurs in patients with respiratory
failure. The
patient may also have severe kidney disease, pulmonary edema, dyspnea, or a
combination thereof. The terlipressin may be administered every 6 hours by IV
bolus
injection over 2 minutes. In some aspects, the method may further comprise
monitoring
the patient's oxygenation level via pulse oximetry during treatment with the
terlipressin.
The monitoring of the oxygenation level decreases the occurrence of adverse
events.
[0038] Some aspects of the disclosure relate to a method of
treating a patient
with hepatorenal syndrome Type 1 (HRS-1) comprising: obtaining a baseline
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oxygenation level (Sp02) via pulse oximetry; administering a dose of
terlipressin to the
patient by intravenous (IV) injection if the patient is not experiencing
hypoxia; and
monitoring the patient's Sp02 during treatment with the terlipressin. The
monitoring of
the oxygenation level may decrease the occurrence of adverse events. In some
aspects, the patient's oxygen saturation is monitored for hypoxia. The method
may
further comprise discontinuing administration or reducing the dose of
terlipressin if
hypoxia is detected. For example, terlipressin may not be administered or may
be
discontinued if the patient's Sp02 at baseline or during treatment is less
than 90%
and/or the patient's Fi02 is greater than 0.36. The patient's Sp02 may be
monitored at
least 3 times a day during administration of terlipressin.
[0039] Even further aspects of the disclosure relate to a
method of treating a
patient with hepatorenal syndrome Type 1 (HRS-1) comprising: administering a
dose of
terlipressin to a patient by intravenous (IV) injection; and discontinuing
administration or
reducing the dose of terlipressin in patients with serum creatinine (SCr) 5
mg/d1.
Additional aspects of the disclosure relate to a method of treating a patient
with
hepatorenal syndrome Type 1 (HRS-1) comprising: measuring a serum creatinine
(SCr)
level in the patient; and administering a dose of terlipressin to the patient
if the patient
has serum creatinine (SCr) <5 mg/di, the patient has an ACLF Grade < 3, or a
combination thereof. The terlipressin may be administered to the patient by
intravenous
(IV) injection. Further aspects of the disclosure include a method of treating
a patient
with hepatorenal syndrome Type 1 (HRS-1) comprising: administering a dose of
terlipressin to a patient by intravenous (IV) injection, wherein
administration does not
occur if the patient has serum creatinine (SCr) 5 mg/di, the patient has an
ACLF
Grade 3, or a combination thereof. In yet another aspect, the invention
comprises a
method of treating a patient with hepatorenal syndrome Type 1 (HRS-1)
comprising:
administering a dose of terlipressin to a patient by intravenous (IV)
injection, wherein
administration occurs only if the patient has serum creatinine (SCr) <5 mg/di,
the
patient has an ACLF Grade < 3, or a combination thereof. The method may
further
include monitoring the patient for fluid overload during treatment with
terlipressin; and
reducing the terlipressin treatment if fluid overload develops. As used
herein, the terms
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"reducing the terlipressin treatment" and "reducing the terlipressin dose" may
comprise
lowering the terlipressin dose, interrupting the terlipressin dose, and/or not
increasing
the dose when the patient is previously prescribed or scheduled for an
increased dose.
Interrupting the terlipressin dose may include temporarily interrupting the
dose until
adverse events subside, until further notice, or until the patient has a serum
creatinine
(SCr) 5 mg/d1. In additional aspects, the method may further comprise
measuring the
SCr level in the patient. In some aspects, the patient's ICU stay, non-ICU
stay, and/or
total length of hospital stay may be shortened. The terlipressin
administration may be
continued until there is a complete response or a partial response.
[0040] In additional aspects, a method of treating a patient
with hepatorenal
syndrome Type 1 (HRS-1) comprises: administering a dose of terlipressin to a
patient
by intravenous (IV) injection; and managing fluid overload by reducing or
discontinuing
the administration of albumin, other fluids, and/or judicious use of
diuretics. As used
herein, judicious use of diuretics means the use of an effective amount of
diuretics. For
clarity, reducing the administration of albumin may comprise lowering the dose
or
interrupting the dose of albumin. If fluid overload persists, the method of
treating may
further comprise reducing or discontinuing terlipressin treatment. In a
further aspect,
managing fluid overload may decrease mortality or the occurrence of adverse
events in
the patient or patient population receiving treatment according to the
invention
described herein. In another aspect, the method of treating a patient with
hepatorenal
syndrome Type 1 (HRS-1) comprises: administering a dose of terlipressin to a
patient
by intravenous (IV) injection; and managing fluid overload by reducing or
discontinuing
the administration of albumin, other fluids, and/or judicious use of
diuretics, wherein the
patient additionally has respiratory failure, severe kidney disease, pulmonary
edema,
dyspnea, tachypnea, ischemia, or a combination thereof.
[0041] In additional aspects, a method of treating a patient
with hepatorenal
syndrome Type 1 (HRS-1) includes administering a dose of terlipressin to a
patient by
intravenous (IV) injection, wherein the dose of terlipressin is not increased
in the
presence of fluid overload, pneumonia, bronchospasm, pulmonary edema, ongoing
significant adverse reactions, preexisting severe coronary artery disease, or
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combinations thereof. In additional aspects, a method of treating a patient
with
hepatorenal syndrome Type 1 (HRS-1) includes administering a dose of
terlipressin to a
patient by intravenous (IV) injection, wherein the dose of terlipressin is
reduced or
discontinued in the presence of fluid overload, pneumonia, bronchospasm,
pulmonary
edema, ongoing significant adverse reactions, preexisting severe coronary
artery
disease, or combinations thereof. Other aspects of the disclosure include a
method of
treating a patient with hepatorenal syndrome Type 1 (HRS-1) comprising:
administering
a dose of terlipressin to a patient every 6 hours by intravenous (IV) bolus
injection over
2 minutes; monitoring the patient for fluid overload during treatment with
terlipressin;
and, reducing or discontinuing the terlipressin treatment if fluid overload
persists.
[0042] Ischemic events (e.g., an inadequate blood supply to
the skin, cardiac,
vascular, or gastrointestinal tissues) may occur following administration of
terlipressin.
The most common ischemia-associated adverse events may comprise included skin
discoloration, cyanosis, intestinal ischemia, and combinations thereof.
Serious ischemic
events in patients treated with terlipressin with may comprise intestinal
ischemia,
vascular skin disorder, cyanosis, livedo reticularis, myocardial infarction,
poor peripheral
circulation, myocardial ischemia, or combinations thereof. Terlipressin should
be used
with caution in patients with a history of ischemic events and certain cardiac
conditions.
In patients who experience signs or symptoms suggestive of ischemic adverse
reactions, terlipressin dose should be reduced or permanently discontinued.
Additional
aspects of the disclosure relate to a method of treating a patient with
hepatorenal
syndrome Type 1 (HRS-1) comprising: administering a dose of terlipressin to a
patient
every 6 hours by intravenous (IV) bolus injection over 2 minutes, wherein the
treatment
of the patient with terlipressin is reduced or discontinued in the presence of
ischemia.
In another aspect, the invention comprises a method of treating a patient with
hepatorenal syndrome Type 1 (HRS-1) comprising: administering a dose of
terlipressin
to a patient every 6 hours by intravenous (IV) bolus injection over 2 minutes,
wherein
the treatment of the patient with terlipressin is reduced or discontinued in
the presence
of skin, cardiac, vascular, or gastrointestinal ischemia, or combinations
thereof in the
patient. The terms "ischemia" and "ischemic events" may be used
interchangeably.
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[0043] Yet other aspects of the disclosure relate to a method
of treating a
patient with hepatorenal syndrome Type 1 (HRS-1) comprising: administering a
dose of
terlipressin to a patient every 6 hours by intravenous (IV) bolus injection
over 2 minutes,
wherein the dose of terlipressin is not increased in the presence of fluid
overload,
pneumonia, bronchospasm, or pulmonary edema. Further aspects of the disclosure
relate to a method of treating a patient with hepatorenal syndrome Type 1 (HRS-
1)
comprising: administering a dose of terlipressin to a patient every 6 hours by
intravenous (IV) bolus injection over 2 minutes; monitoring the patient for
fluid overload
during treatment with terlipressin; and, reducing or discontinuing the dose of
terlipressin
if fluid overload develops. In yet another aspect of the disclosure, a method
of treating a
patient with hepatorenal syndrome Type 1 (HRS-1) includes: administering a
dose of
terlipressin to a patient every 6 hours by intravenous (IV) bolus injection
over 2 minutes,
wherein the treatment with terlipressin is immediately interrupted in the
presence of
treatment-emergent pulmonary edema, new onset or worsening pneumonia, or
unresolved hepatic encephalopathy Grade 3 with risk of aspiration.
[0044] Further aspects of the disclosure relate to a method of
increasing
overall survival or a patient with hepatorenal syndrome Type 1 (HRS-1), the
method
comprising: measuring a serum creatinine (SCr) level in the patient; and
administering a
dose of terlipressin to the patient if the patient has serum creatinine (SCr)
<5 mg/di.
More aspects of the disclosure relate to a method of decreasing an overall ICU
or
hospital stay of a patient with hepatorenal syndrome Type 1 (HRS-1), the
method
comprising: measuring a serum creatinine (SCr) level in the patient; and
administering a
dose of terlipressin to the patient if the patient has SCr < 5 mg/d1.
[0045] Additional aspects of the disclosure relate to a method
of increasing a
complete response of a patient with hepatorenal syndrome Type 1 (HRS-1), the
method
comprising: measuring a serum creatinine (SCr) level in the patient;
administering a
dose of terlipressin to a patient by intravenous (IV) injection if the
patient's SCr level is <
mg/di; and continuing administration of terlipressin until the patient's SCr
level is
mg/d1. Yet further aspects of the disclosure relate to a method of increasing
a partial
response of a patient with hepatorenal syndrome Type 1 (HRS-1), the method
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comprising: measuring a serum creatinine (SCr) level in the patient;
administering a
dose of terlipressin to a patient by intravenous (IV) injection if the
patient's SCr level is <
mg/di; and continuing administration of terlipressin until the patient
experiences
greater than 20% improvement in serum creatinine.
[0046] Additional aspects and features are set forth in part
in the description
that follows, and will become apparent to those skilled in the art upon
examination of the
specification or may be learned by the practice of the disclosed subject
matter.
BRIEF DESCRIPTION OF THE DRAWINGS
[0047] Further features of embodiment of the present
disclosure, their nature
and various advantages will become more apparent upon consideration of the
following
detailed description, taken in conjunction with the accompanying drawings,
which are
also illustrative of the best mode contemplated by the applicants, and in
which like
reference characters refer to like parts throughout, where:
[0048] FIG. 1 illustrates an exemplary embodiment of a
terlipressin treatment
protocol;
[0049] FIG. 2 illustrates an exemplary embodiment of a
terlipressin treatment
protocol;
[0050] FIG. 3 illustrates a set of unexpected results from an
exemplary
embodiment of a terlipressin treatment protocol;
[0051] FIG. 4 illustrates an exemplary embodiment of a
terlipressin treatment
protocol;
[0052] FIG. 5 is a graph showing 90-day survival of patients
treated with and
without terlipressin according to ACLF grade;
[0053] FIG. 6A shows the percentage of patients with renal
failure at baseline
and end of treatment for patients treated with terlipressin and placebo;
[0054] FIG. 6B shows the percentage of patients with
respiratory failure at
baseline and end of treatment for patients treated with terlipressin and
placebo; and
[0055] FIG. 6C shows the percentage of patients with
respiratory failure with
ACLF Grade 2 and ACLF Grade 3 for patients treated with terlipressin and
placebo.
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DETAILED DESCRIPTION
[0056] The principles and embodiments of the present
disclosure relate to
methods of improving a patient's renal condition involving a treatment
protocol
comprising terlipressin. Accordingly, various embodiments of the present
disclosure
provide methods of treating a patient with terlipressin or terlipressin and
albumin.
[0057] As used herein, use of "terlipressin" may refer to
terlipressin or salts,
diacetate salts, hydrates, and/or free bases thereof. For example, use of
terlipressin
may include terlipressin acetate or terlipressin diacetate pentahydrate. In
additional
examples, terlipressin may refer to any other suitable salts or hydrates
thereof or any
other biologically acceptable salts or hydrates thereof.
[0058] As used herein, the terms "reducing the terlipressin
treatment" and
"reducing the terlipressin dose" may comprise lowering the terlipressin dose,
interrupting the terlipressin dose, and/or not increasing the dose when the
patient is
previously prescribed or scheduled for an increased dose. Interrupting the
terlipressin
dose may include temporarily interrupting the dose until adverse events
subside, until
further notice, or until the patient has a serum creatinine (SCr) 5 mg/d1.
[0059] As used herein, the "mitigated population" or "subset
of patients"
includes HRS-1 patients with a baseline ACLF Grade 0-2, a baseline serum
creatinine <
mg/dL, and/or a baseline MELD <35. For example, the mitigated population
excludes
patients with baseline ACLF Grade 3, baseline serum creatinine mg/dL,
and/or
patients listed for transplant at baseline with a baseline MELD
[0060] In embodiments of the present disclosure, the patient
is evaluated to
determine the particular disease and/or syndrome he or she may be suffering
from, and
beginning a treatment regimen for patients that will benefit from the
administration of
terlipressin.
[0061] In various embodiments, the patient has end stage liver
disease
complicated with acute kidney failure, such as HRS, and is treated with
terlipressin.
[0062] In various embodiments, end-stage liver disease may be
cirrhosis of
the liver or fulminant liver failure. In various embodiments, the end-stage
liver disease is
complicated by impaired renal function.
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[0063] HRS-1 in decompensated cirrhosis is related to
hemodynamic
abnormalities. Terlipressin improves renal perfusion in HRS-1 by enhancing
intravascular volume through splanchnic vasoconstriction. In some aspects,
terlipressin
may be more effective than placebo in albumin-treated patients with
decompensated
cirrhosis and HRS-1. An aspect of the present disclosure relates to a method
of
diagnosis of patients that show improved response to terlipressin treatment,
as
indicated by an increased probability of HRS reversal.
[0064] In one or more embodiments, the method of identifying
an HRS-1
patient with an increased likelihood of responding to terlipressin treatment
regimen
comprises identifying a patient as having end stage live disease and impaired
renal
function, determining if the patient also exhibits at least two out of three
criteria for
SIRS, wherein the three response criteria include (1) a white blood cell count
(WBC)
that is less than 4,000 cells/mm3or greater than 12,000 cells/mm, (2) a heart
rate of
greater than 90 beats per minute (BPM), and (3) an HCO3<21 mmol/L, where HCO3
is
considered a surrogate measurement that approximates the response criteria of
arterial
partial pressure of carbon dioxide (PaCO2)<32 mmHg. In various embodiments, a
heart
rate of >85 BPM and/or an HCO3<23 mmol/L may be applied as the response
criteria.
[0065] An aspect of the present disclosure relates to
terlipressin for use in the
treatment of HRS-1 in a subject that is also exhibiting at least two of the
following three
response criteria:
(a) a white blood cell count (WBC) is less than 4,000 cells/mm3or greater than
12,000
cells/mm,
(b) a heart rate of greater than 90 beats per minute (BPM), and
(c) an HCO3<21 mmol/L, where HCO3 is considered a surrogate measurement that
approximates the response criteria of arterial partial pressure of carbon
dioxide
(PaCO2)<32 mmHg. In various embodiments, one or more single dosages of
terlipressin
is administered to the subject, thereby treating the HRS-1.
[0066] In various embodiments, the terlipressin dosage is
administered to the
patient in the range of about 0.5 mg to about 2.0 mg every 4 to 6 hours, as a
series of
single doses, so that the patient receives a single dose in the range of about
0.5 mg to
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about 2.0 mg of terlipressin followed by another single dose 4 to 6 hours
later. In
various embodiments, a patient may receive 4 to 6 doses over a 24 hour period,
where
each dose is in the range of about 0.5 mg to about 2.0 mg. In various
embodiments, the
total dosage does not exceed 4.0 mg over a 24 hour period.
[0067] As shown in FIG. 1, an exemplary embodiment of a method
of treating
a patient via an embodiment of a terlipressin treatment protocol.
[0068] In various embodiments, a patient, who is initially
identified as having
end stage liver disease, for which treatment with a vasodilator may provide an
improvement in renal function, is tested to determine the extent of the
patient's cirrhosis
and renal failure.
[0069] At 110, a patient is initially identified as having end
stage liver disease
and impaired renal function. In various embodiments, a patient may be
suffering from
cirrhosis of the liver or fulminant liver failure, where a patient identified
with cirrhosis of
the liver may have a Child-Pugh score of A, B, or C. In various embodiments, a
patient
identified with cirrhosis of the liver that has a Child-Pugh score of B or C
may be
considered a viable candidate for terlipressin treatment. In various
embodiments, a
patient identified with cirrhosis of the liver that has a Child-Pugh score of
C may be
considered a viable candidate for terlipressin treatment. Various
complications of end-
stage liver disease, and in particular cirrhosis, are recognized and have a
notably poor
prognosis.
[0070] In one or more embodiments, a treatment protocol
comprising dosages
of terlipressin surprisingly provides reversal of one or more complicating
factors, such
as vasodilation, and reduces mortality from the associated complications
within a 90
day window starting with treatment.
[0071] In one or more embodiments, the terlipressin treatment
protocol
comprises identifying a patient having end-stage liver disease and impaired
renal
function, where the identified patient may benefit from a treatment comprising
administration of terlipressin, determining if the patient also exhibits at
least two out of
three response criteria, excluding the patient from administration of
terlipressin if the
patient exhibits uncontrolled infection, sepsis, or septic shock is excluded
from the
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terlipressin treatment, and initiating terlipressin treatment by administering
a daily
dosage of terlipressin to the patient in an amount effective to produce an
improvement
in renal function, wherein an improvement in renal function is indicated by a
reduction in
SCr of at least 25% from baseline, reversal of HRS (defined as a decrease in
SCr level
to mg/di), and/or confirmed HRS reversal (defined as two serum
creatinine values
of mg/dL at least 48 hours apart)).
[0072] In one or more embodiments, the patient is alive at day
90 after
initiating terlipressin treatment. For example, a patient that experiences HRS
reversal,
verified HRS reversal, and/or greater than 30% improvement in SCr after
receiving
terlipressin may have at least a 60%, 65%, or 70% likelihood of being alive at
day 90.
In other embodiments, the patient is alive and transplant-free at day 90 after
initiating
terlipressin treatment. For example, a patient that experiences HRS reversal,
verified
HRS reversal, and/or greater than 30% improvement in SCr after receiving
terlipressin
may have at least a 35%, 40%, or 45% likelihood of being alive and transplant-
free at
day 90.
[0073] In one or more embodiments, the terlipressin dosage may
be in the
range of about mg to about 10 mg, or 0.5 mg to about 5.0 mg, or 0.5 mg to
about 2.0
mg, or 0.5 mg to about mg, or about 1.0 mg to about 2.0 mg per single
administration.
In various embodiments, the injections may be administered intravenously as
slow
bolus injections over 2 minutes, where the dose may be repeated every four to
six
hours. If on day 4 of therapy (after a minimum of 10 doses), SCr had
decreased, but by
less than 30% from the baseline value, the dose may be increased to 2 mg every
6
hours ( 30 min) (8 mg/day). The dose may not be increased if the subject had
coronary
artery disease; or in the clinical setting of circulatory overload, pulmonary
edema, or
treatment-refractory bronchospasm. The terms "circulatory overload" and "fluid
overload" may be used interchangeably. In various embodiments, if dosing was
interrupted due to a non-ischemic adverse event, terlipressin may be restarted
at the
same or lower dose (i.e., 0.5 to 1 mg q6h).
[0074] At 180, a patient that is not diagnosed with an end-
stage liver disease
and impairment of renal function is excluded from the terlipressin treatment.
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[0075] In one or more embodiments, the patient is tested for
three specific
response criteria, where the criteria include a determination of (1) whether
the white
blood cell count (WBC) is less than 4,000 cells/mm3or greater than 12,000
cells/mm3,
(2) whether the patient has a heart rate of greater than 90 beats per minute
(BPM),
and/or (3) whether the patient has tachypnea with greater than 20 breaths per
minute or
an HCO3<21 mmol/L, where HCO3 is considered a surrogate measurement that
approximates the response criteria of arterial partial pressure of carbon
dioxide
(PaCO2)<32 mmHg. In various embodiments, the response criterion of a patient's
core
body temperature being less than 36 C. (96.8 F.) or greater than 38 C.
(100.4 F.) is
not measured or considered in determining if the patient has two or more
response
criteria. In some examples, the response criteria may be SIRS criteria. In
various
embodiments, the criteria may be tested in any order.
[0076] At 120, a patient is tested to determine if the
patient's WBC is <4,000
or >12,000 cells/mm3. In various embodiments, the testing is specifically
directed at
determining if the patient's leukocytes are less than 4000 cells/mm3(4x109
cells/L) or
greater than 12,000 cells/mm3(12x109 cells/L). In various embodiments, a
patient will be
considered to meet the response criterion if the patient's WBC is <5,000 or
>12,000
cells/mm3. In various embodiments, the patient is not tested for the presence
of greater
than 10% immature neutrophils (band forms). In various embodiments, the
testing
method to determine the WBC may be any of the methods known in the art.
[0077] If the patient is found to not have a WBC outside the
range of 4,000 to
12,000 cells/mm3, the patient may still be diagnosed with SIRS if the patient
meets the
two other response criteria.
[0078] In various embodiments, a patient that has a WBC<4,000
or >12,000
cells/mm3 is considered to meet that response criterion.
[0079] At 130, a patient that does not have a WBC outside the
range of 4,000
to 12,000 cells/mm3 is tested to determine if the patient's heart rate is >90
BPM. If the
patient's heart rate is >90 BPM, the patient will be considered to meet that
response
criterion. In various embodiments, a patient with a heart rate of >85 BPM will
be
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considered to meet that response criterion. The testing method to determine
the
patient's heart rate may be any of the methods known in the art.
[0080] In various embodiments, a patient that has a VVBC
outside the range of
5,000 to 12,000 cells/mm3 is tested to determine if the patient's heart rate
is >90 BPM. If
the patient's heart rate is >90 BPM, the patient will be considered to meet
that response
criterion. In various embodiments, a patient with a heart rate of >85 BPM will
be
considered to meet that response criterion.
[0081] At 185, a patient that does not exhibit both a
WBC<4,000 or >12,000
cells/mm3 and a heart rate that is >90 BPM is considered to not qualify for
two of the
three response criteria, and therefore does not meet the requirements to be
treated with
terlipressin. A patient failing to meet at least two of the three response
criteria is
excluded from the terlipressin treatment. Such a patient may be treated
instead with one
or more other pharmacological agents such as nor-epinephrine, vasopressin, or
a
combination of midodrine and octreotide. Alternatively or in addition, any of
the following
may be used: N-acetylcysteine, misoprostol, and/or BQ123. Another option is
transjugular intrahepatic portosystemic shunt (TIPS). Renal support in the
form of
dialysis is commonly instituted to manage acute fluid overload in HRS-1
patients,
particularly if pharmacological therapies fail. The only effective and
permanent
treatment for end-stage cirrhosis and HRS is liver transplantation.
[0082] At 140, a patient that has a WBC outside the range of
4,000 to 12,000
cells/mm3 or a heart rate that is >90 BPM is tested to determine if the
patient has >20
breaths per minute or an HCO3<21 mmol/L. If the patient has >20 breaths per
minute or
an HCO3<21 mmol/L, the patient will be considered to meet that response
criterion. In
various embodiments, a patient with an HCO3<23 mmol/L will be considered to
meet
that response criterion. The testing method to determine the patient's
breathing rate or
HCO3 may be any of the methods known in the art.
[0083] In various embodiments, a patient that has a VVBC
outside the range of
5,000 to 12,000 cells/mm3 is tested to determine if the patient has a
breathing rate that
is >20 breaths per minute or an HCO3<21 mmol/L. If the patient has a breathing
rate
that is >20 breaths per minute or an HCO3<21 mmol/L, the patient will be
considered to
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meet that response criterion. In various embodiments, a patient with an
HCO3<23
mmol/L will be considered to meet that response criterion.
[0084] In one or more embodiments, if the patient has a WBC
outside the
range of 4,000 to 12,000 cells/mm3 and the patient has >20 breaths per minute
or an
HCO3<21 mmol/L, the patient is considered to qualify for two of the three
response
criteria, and therefore meets the requirements to be treated with terlipressin
unless
otherwise excluded.
[0085] In one or more embodiments, if the patient has a heart
rate that is >90
BPM and the patient has a breathing rate that is >20 breaths per minute or an
HCO3<21
mmol/L, the patient is considered to qualify for two of the three response
criteria, and
therefore meets the requirements to be treated with terlipressin unless
otherwise
excluded.
[0086] At 135, a patient that has a WBC outside the range of
4,000 to 12,000
cells/mm3, but does not have >20 breaths per minute or an HCO3<21 mmol/L, is
tested
to determine if the patient's heart rate is >90 BPM. If the patient's heart
rate is >90 BPM,
the patient will be considered to meet that response criterion. In various
embodiments, a
patient with a heart rate of >85 BPM will be considered to meet that response
criterion.
[0087] In one or more embodiments, in which the patient has a
WBC outside
the range of 5,000 to 12,000 cells/mm3, but the patient does not have >20
breaths per
minute or an HCO3<21 mmol/L, the patient is tested to determine if the
patient's heart
rate is >90 BPM. If the patient's heart rate is >90 BPM, the patient will be
considered to
meet that response criterion. In various embodiments, a patient with a heart
rate of >85
BPM will be considered to meet that response criterion.
[0088] In one or more embodiments, if the patient has a
breathing rate that is
>20 breaths per minute or an HCO3<21 mmol/L a heart rate that is >90 BPM and
the
patient has a breathing rate that is >20 breaths per minute or an HCO3<21
mmol/L, the
patient is considered to qualify for two of the three response criteria, and
therefore
meets the requirements to be treated with terlipressin unless otherwise
excluded.
[0089] At 186, a patient that does not exhibit (1) a breathing
rate that is >20
breaths per minute or an HCO3<21 mmol/L and does not exhibit (2) a heart rate
that is
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>90 BPM is considered to not qualify for at least two of the three response
criteria, and
therefore does not meet the requirements to be treated with terlipressin. A
patient failing
to meet at least two of the three response criteria is excluded from the
terlipressin
treatment. Optional alternative treatments for such a patient are described
above.
[0090] While the tests for the response criteria have be
discussed in a
particular order for the exemplary embodiment, the tests may be done in any
particular
order.
[0091] In one or more embodiments, temperature is not a
response criterion
because patient temperature may not provide an accurate indication of patient
response
to terlipressin. In various embodiments, patient temperatures are excluded
from the set
of response criteria.
[0092] At 150, a patient that has end stage liver disease with
impaired renal
function, and qualifies for at least two of the three response criteria, is
started on
terlipressin. In one or more embodiments, a patient with uncontrolled
infection, sepsis,
or septic shock is excluded from the terlipressin treatment. In various
embodiments,
terlipressin is administered to the patient for one to four days. In various
embodiments,
the patient is administered terlipressin for four days unless the patient
experiences an
adverse event. In various embodiments, the terlipressin is administered to the
patient as
an IV drip.
[0093] In one or more embodiments, the terlipressin treatment
protocol
comprises administering a dosage of terlipressin in the range of about 0.1 mg
to about
mg, or 0.5 mg to about 5.0 mg, or 0.5 mg to about 2.0 mg, or about 0.5 mg to
about
1.0 mg, or about 1.0 mg to about 2.0 mg to the patient over about four hours
to about
six hours as an IV drip.
[0094] In one or more embodiments, the patient is administered
terlipressin as
an IV about every 4 to 6 hours for 1 to 4 days. In various embodiments, the
terlipressin
may be administered for at least 4 days.
[0095] In one or more embodiments, the patient is administered
terlipressin as
a slow bolus over 2 minutes about every 4 to 6 hours for 1 to 4 days. In
various
embodiments, the terlipressin may be administered for at least 4 days.
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[0096] At 160, the patient that is being administered the
terlipressin is tested
at least once during the one to four day period of administration to determine
if the
patient is responding to the terlipressin. In various embodiments, the patient
may be
tested once prior to beginning the administration of the terlipressin to
establish a
baseline and once during the one to four days of terlipressin administration,
or once
prior to beginning the administration of the terlipressin to establish a
baseline and once
at the end of the four days of administration of the terlipressin. In various
embodiments,
the patient's creatinine levels are measured to determine if there has been a
reduction
in the patient's serum creatinine, where a reduction in serum creatinine
levels of about
1.0 mg/dL or greater, or in the range of about 1.0 mg/dL to about 2.0 mg/dL,
or a
reduction of about 1.7 mg/dL from the patient's initial baseline value
indicates an
improvement in renal function and that the patient is responding to the
terlipressin.
[0097] In various embodiments, improvement in renal function
is indicted by a
decrease in serum creatinine level of about 25% or about 30% in the patient
receiving
terlipressin.
[0098] In one or more embodiments, a patient may have his or
her serum
creatinine levels measured once a day or once every other day for each of the
four day
period after administration of terlipressin has begun, wherein a measurement
made on
the first day of terlipressin administration may be recorded and used as the
baseline
creatinine level.
[0099] In various embodiments, the method may comprises
testing the
patient's SCr level during the 1 to 4 days of terlipressin administration and
determining if
the patient has a reduction in SCr level by the end of the 1 to 4 days of
terlipressin
administration.
[00100] The serum creatinine levels may be measured by any of the methods
known in the art, for example, the Jaffe reaction using alkaline picrate.
[00101] The GFR may be measured directly by clearance studies of
exogenous markers, such as inulin, iohexol, iothalamate, and Cr51-EDTA, or by
estimated glomerular filtration rate (eGFR) using creatinine testing methods
that are
traceable to a reference method based on isotope dilution-mass spectrometry
(IDMS).
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[00102] At 170, a patient that shows a positive response to the administration
of the terlipressin evidenced by a reduction in the patient's serum creatinine
level is
continued on the terlipressin at the dosage in the range of about 0.1 mg to
about 10 mg,
or 0.5 mg to about 5.0 mg, or 0.5 mg to about 2.0 mg, or about 0.5 mg to about
1.0 mg,
or about 1.0 mg to about 2.0 mg. In various embodiments, the dosage
administered to
the patient may be adjusted based upon the measured serum creatinine level(s).
In
various embodiments, a patient being administered terlipressin may have their
serum
creatinine levels monitored for the entire time period that the patient is
receiving
terlipressin. In one or more embodiments, the patient's serum creatinine level
may be
tested every day, or every other day, or every third day, or every fourth day,
to confirm
that the patient is still responding positively to the terlipressin treatment.
[00103] In various embodiments, the patient's terlipressin dosage may be
increased from about 0.5 mg to about 1.0 mg to about 1.0 mg to about 2.0 mg
after 2-3
days of terlipressin administration to the patient if there is <1.5 mg/dL
decrease in SCr
during the first 2-3 days of treatment.
[00104] In various embodiments, the dosage may be repeated every four to six
hours for a time period of one or more days until the patient shows recovery,
or until the
patient no longer shows improvement. The terlipressin may be administered to
the
patient for a time period in the range of about two days to about sixteen
days, or for a
time period in the range of about four days to about eight days. In various
embodiments,
the time period is in the range of about seven days. In various embodiments,
the
terlipressin treatment may be continued until there is a complete response. In
various
embodiments, the duration of treatment of a patient with terlipressin may be 1
to 28
days.
[00105] At 190, a patient that does not show any improvement by the end of
four days may have the terlipressin discontinued, where improvement is
indicated by a
decrease in serum creatinine levels over the one to four days the terlipressin
is
administered. In various embodiments the patient may be tested on the third or
fourth
day after starting treatment with the terlipressin to determine if there is a
decrease in
serum creatinine levels indicating a response to the treatment.
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[00106] In one or more embodiments, a patient is provided 2 days of anti-
infective therapy for documented or suspected infection before starting
administration of
terlipressin if an infection is suspected. In various embodiments, a patient
may be
started on the terlipressin treatment protocol after the patient has been
administered the
anti-infective therapy.
[00107] FIG. 2 illustrates an exemplary embodiment of a terlipressin treatment
protocol.
[00108] Principles and embodiments of the present disclosure also relate to
providing terlipressin as an IV every four to six hours to patients that have
been
identified with HRS-1 and two or more of three specific response criteria.
[00109] In one or more embodiments, a patient is tested for (1) a white blood
cell count (WBC) <4 or >12 cells/pL; (2) a heart rate (HR)>90 beats per minute
(bpm),
and (3) HCO3<21 mmol/L.
[00110] A non-SIRS patient is defined as subjects with <2 of the response
criteria described above.
[00111] In various embodiments, temperature is not used as a response
criterion.
[00112] In one or more embodiments of the disclosure, terlipressin is
administered to patients presenting with a particular set of symptoms to
mitigate the
vasoconstriction in the kidneys, and improve renal function as indicated by a
reduction
in serum creatinine levels of about 1.7 mg/dL from initial baseline.
[00113] At 210, one or more patients that may be presenting with end-stage
liver disease are tested to determine whether they are suffering from
cirrhosis with
ascites, and have serum levels of creatinine>133 pmo1/1. A patient identified
as having
HRS is further tested and/or their medical history checked to determine if the
initial
serum levels of creatinine have doubled to greater than 226 pmo1/1 in less
than 2 weeks
indicating type 1 HRS.
[00114] Patients having HRS-1 and at least two of three response criteria have
surprisingly shown improved response to terlipressin treatment compared to non-
SIRS
HRS-1 patients, as indicated by reversal of the HRS indications. In addition,
patients
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having HRS-1, at least two of three response criteria, and not having
uncontrolled
infection, sepsis, or septic shock have surprisingly shown improved response
to
terlipressin treatment compared to non-SIRS HRS-1 patients. The HRS
indications may
include serum creatinine levels.
[00115] The patients having HRS-1 and SIRS may experience HRS reversal,
verified HRS reversal, or greater than 30% improvement in SCr after receiving
terlipressin. In one or more embodiments, the patent is alive at day 90 after
initiating
terlipressin treatment. For example, a patient that experiences HRS reversal,
verified
HRS reversal, and/or greater than 30% improvement in SCr after receiving
terlipressin
may have at least a 60%, 65%, or 70% likelihood of being alive at day 90. In
other
embodiments, the patient is alive and transplant-free at day 90 after
initiating terlipressin
treatment. For example, a patient that experiences HRS reversal, verified HRS
reversal,
and/or greater than 30% improvement in SCr after receiving terlipressin may
have at
least a 35%, 40%, or 45% likelihood of being alive and transplant-free at day
90.
[00116] At 220, once a patient has been identified as suffering from HRS-1,
the
patient is tested to determine is the same patient is exhibiting at least two
out of three
criteria indicating SIRS, wherein the three criteria include a (1) WBC<4 or
>12 cells/pL;
(2) HR>90 bpm, and (3) HCO3<21 mmol/L.
[00117] In various embodiments, patients not identified as exhibiting at least
two of the three response criteria in addition HRS-1 are excluded from the
terlipressin
treatment protocol. Patients having HRS-1 and exhibiting at least two of the
three
response criteria have surprisingly shown improved response to terlipressin
treatment
compared to non-SIRS HRS-1 patients, as indicated by reversal of the HRS
indications,
as shown in FIG. 3.
[00118] At 230, patients that have been identified as having HRS-1 and exhibit
at least two response criteria are tested to determine if they may also have
an
uncontrolled infection, sepsis, or septic shock, wherein patients identified
as exhibiting
an uncontrolled infection, sepsis, or septic shock are excluded from the
terlipressin
treatment protocol.
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[00119] At 240, patients that have HRS-1, have at least two of the three
response criteria, and do not have an uncontrolled infection, sepsis, or
septic shock are
started on the terlipressin treatment. In one or more embodiments, the
terlipressin
treatment is started within 48 hours of the initial diagnosis that the patient
has both
HRS-1 and at least two of three response criteria. In various embodiments, in
which the
determination that the patient does or does not also have an uncontrolled
infection,
sepsis, or septic shock occurs after 48 hours of the initial diagnosis of both
HRS-1 and
the response criteria, the treatment protocol is started within 48 hours of
the initial
diagnosis, and treatment may be terminated once an uncontrolled infection,
sepsis, or
septic shock manifests or is determined.
[00120] In various embodiments, a baseline serum creatinine level may be
determined for the patient prior to starting the administration of
terlipressin to the
patient; and the administration of terlipressin started within 2 days or
within 3 days, or
within 4 days of determining the baseline serum creatinine level. In various
embodiments, the patient may be tested at least once daily within four days
after
starting the administration of terlipressin to determine if the patient
exhibits a decrease
in the serum creatinine level compared to the previously determined baseline
serum
creatinine level.
[00121] At 250, terlipressin treatment of the patient is started and the
patient
receives a dosage of terlipressin. In one or more embodiments, the
terlipressin may be
administered to a patient as a slow infusion over 24 hours, wherein the dosage
over the
24 hour period may be in the range of about 2.0 mg to about 12 mg. In various
embodiments, the dosage over the 24 hour period may be in the range of about
2.0 mg
to about 4.0 mg. In various embodiments, the terlipressin is administered as a
continuous intravenous (IV) drip lasting from about 4 hours to about 6 hours,
and
comprising a dosage of about 0.5 mg to about 2.0 mg.
[00122] In one or more embodiments, the terlipressin dosage may be a dosage
of about 0.5 mg to about 2.0 mg administered intravenously every 4 to 6 hours
as a
slow bolus injection over 2 minutes. The dosage may be administered about
every 4
hours, about every 5 hours, about every 6 hours, about every 7 hours, about
every 8
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hours, about every 9 hours, about every 10 hours, about every 11 hours, or
about every
12 hours by slow IV bolus injection. In at least one example, the dosage may
be
administered about every 6 hours by slow IV bolus injection. The bolus
injection may be
given over about 1 minute, about 2 minutes, about 3 minutes, about 4 minutes,
or about
minutes. In at least one example, the bolus injection may be given over about
2
minutes.
[00123] In one or more embodiments, the terlipressin is used to treat the
patient exhibiting HRS-1 and at least two of the three response criteria. In
various
embodiments, the patient is also tested to determine that the patient does not
have an
uncontrolled infection, sepsis, or septic shock before being using the
terlipressin to treat
the HRS-1 patient.
[00124] In various embodiments, the terlipressin dosage is given as a
continuous IV feed.
[00125] In one or more embodiments, the terlipressin dosage is 1 mg
administered intravenously every 6 hours as a slow bolus injection over 2
minutes.
[00126] In various embodiments, the terlipressin dosage is not given as a
bolus.
[00127] The terlipressin may be administered to the patient for up to 4 days,
wherein the patient may be tested each day of the four days to determine
whether the
patient is responding to the terlipressin treatment. In various embodiments, a
response
to the terlipressin treatment may be indicated by a change in the patient's
serum
creatinine levels, where indication may be a reduction in SCr of at least 25%
from
baseline. In various embodiments, the terlipressin may be administered for at
least 4
days.
[00128] At 260, the amount of serum creatinine change is determined after 4
days of treatment with terlipressin, and the treatment with terlipressin
continued if the
serum creatinine level has improved. In various embodiments, a sufficient
improvement
in serum creatinine levels after 4 days of treatment is indicated by a
decrease of at least
1.0 mg/dL in serum creatinine level, or a decrease of about 1.7 mg/dL in serum
creatinine level.
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[00129] In various embodiments, the patient receives terlipressin for an
additional 3 days to 8 days if improvement was exhibited over the previous 1
to 4 days.
In various embodiments, the patient receives terlipressin for an additional 3
days to 4
days if improvement was exhibited over the previous 1 to 4 days.
[00130] In various embodiments, the administration of terlipressin to the
patient
is continued for an additional 3 days to 12 days beyond the initial 4 days if
the patient
exhibits a decrease in the serum creatinine level. In various embodiments,
administration of terlipressin to the patient may be continued until at least
one SCr
value<1.5 mg/dL is obtained. In various embodiments, the duration of treatment
may be
extend to a maximum of 15 days or 16 days if HRS reversal was first achieved
on days
13 or 14, respectively. In various embodiments, the duration of treatment of a
patient
with terlipressin may be 1 to 28 days. In various embodiments, a decrease in
the serum
creatinine level may be indicated by a reduction in SCr of at least 1% or of
at least 5%
or at least 10% or at least 15% or at least 20% or at least 25% from baseline.
[00131] In one or more embodiments, the patient may have been administered
albumin prior to beginning the terlipressin treatment protocol, and/or prior
to the
determination that the patient has HRS-1, at least two of the three response
criteria. In
various embodiments, albumin may be administered to a patient 7 days to 2 days
before starting administration of terlipressin to the patient. In various
embodiments, the
albumin treatment comprises administering 1 gram albumin per 1 kg of patient
weight
up to a maximum of 100 g per day of albumin to a patient. In various
embodiments,
albumin may be administered in the range of about 20 g/day to about 50 g/day,
where
the albumin may be administered for the time period that the patient is
administered
terlipressin.
[00132] A non-limiting embodiment of a method of treating HRS-1 patients
exhibiting at least two of three response criteria with terlipressin comprises
administering to a patient in need of such treatment a dosage of terlipressin
in the range
of 2.0 mg to 12.0 mg per day for 1 to 28 days, or in the range of 2.0 mg to
4.0 mg per
day for 1 to 7 days, wherein the dosage may be administered as a continuous IV
feed or
as a slow bolus injection.
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[00133] Embodiments of the present disclosure also relate to treating patients
with HRS-1 and meeting two or more response criteria with one dose of
terlipressin
every six hours, where the dose is in the range of about 0.5 mg to 2.0 mg, for
3 to 8
days to achieve reversal of the HRS-1.
[00134] Embodiments of the present disclosure also relate to initiating
terlipressin treatment within 48 hours of determining that a patient is
presenting with
HRS-1 and at least two of three response criteria, but without sepsis, septic
shock, or
uncontrolled infection.
[00135] Another aspect of the present disclosure relates to a method of
distributing a pharmaceutical product.
[00136] In one or more embodiments, the method of distributing comprises
supplying terlipressin to a medical provider, where the medical provider may
be
responsible for treating a patient suffering from type 1 hepatorenal syndrome.
In various
embodiments, the patient does not have overt sepsis, septic shock, or
uncontrolled
infection. In various embodiments, the method includes providing a
recommendation to
the medical provider to treat the patient suffering from type 1 hepatorenal
syndrome that
does not have overt sepsis, septic shock, or uncontrolled infection and having
at least
two of (1) a white blood cell count (WBC) is less than 4,000 cells/mm3or
greater than
12,000 cells/mm, (2) a heart rate of greater than 90 beats per minute (BPM),
or (3) an
HCO3<21 mmol/L, with terlipressin in an amount effective to reduce SCr. In one
or more
embodiments, the medical provider follows the recommendation and administers a
treatment to the patient suffering from HRS-1, but not overt sepsis, septic
shock, or
uncontrolled infection and having at least two of (1) a white blood cell count
(WBC) is
less than 4,000 cells/mm3or greater than 12,000 cells/mm, (2) a heart rate of
greater
than 90 beats per minute (BPM), or (3) an HCO3<21 mmol/L, with terlipressin in
an
amount effective to reduce SCr.
[00137] The efficacy of terlipressin versus placebo in achieving verified HRS-
1
reversal may be more pronounced among the subgroup of patients with systemic
inflammatory response syndrome (SIRS). Inflammatory cytokines have been
implicated
in the pathogenesis of HRS-1. Without being limited to any one theory,
terlipressin,
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through its ability to reduce portal pressure, may decrease the extent of
bacterial
translocation across the gut wall of patients with decompensated cirrhosis,
with
consequent reduction in endotoxemia and decrease in the production of pro-
inflammatory cytokines, hence making it easier for the patients to respond to
the
hemodynamic effects of terlipressin.
[00138] FIG. 3 shows the unexpected results produced by an exemplary
treatment protocol.
[00139] An aspect of the present disclosure relates to methods of treating
and/or reversing HRS-1. As shown in FIG. 4, an exemplary embodiment of a
method of
treating an adult patient with HRS-1 via an embodiment of a terlipressin
treatment
protocol.
[00140] In various embodiments, a patient, who is initially identified as
having
end stage liver disease, for which treatment with a vasodilator may provide an
improvement in renal function, may be tested to determine the extent of the
patient's
cirrhosis and renal failure. In an embodiment, the patient to be treated is an
adult patient
that has been diagnosed with HRS-1.
[00141] In one or more embodiments, the method of treating an adult patient
with type 1 hepatorenal syndrome (HRS-1) includes assessing a baseline serum
creatinine (SCr) level prior to administration of terlipressin to the patient,
initiating dosing
of about 0.5 mg to about 1 mg of terlipressin to the patient every 6 hours by
IV for 1-3
days, assessing a serum creatinine level in the patient at day 4 1 day from
initiating
dosing; and administering a modified dosage of terlipressin based on a
comparison of
the assessed serum creatinine level at day 4 1 day and the baseline serum
creatinine
level. In some embodiments, the method may further include continuing
administration
until 24 hours after two consecutive serum creatinine levels of 1.5 mg/dL at
least 2
hours apart for a maximum of 14 days.
[00142] In one or more embodiments, the terlipressin dosage may be in the
range of about 0.1 mg to about 10 mg, about 0.5 mg to about 10 mg, or 0.5 mg
to about
5.0 mg, or 0.5 mg to about 2.0 mg, or 0.5 mg to about 1.0 mg, about 0.85 mg to
about
1.7 mg, or about 1.0 mg to about 2.0 mg per single administration.
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[00143] In an embodiment, the terlipressin administered may be terlipressin
acetate. The terlipressin acetate dosage may be administered to the patient in
the range
of about 0.5 mg to about 2.0 mg. In various examples, the terlipressin acetate
dosage
may be about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about
3
mg, about 3.5 mg, or about 4 mg.
[00144] The terlipressin may be prepared for injection as a white to off-white
lyophilized powder in a single-dose vial for reconstitution at a dosage of
0.85 mg
terlipressin (equivalent to 1 mg terlipressin acetate). In some embodiments,
the
terlipressin acetate dosage may be given at an initial dose of about 0.5 mg or
about 1
mg. In at least one example, dosing may be initiated with 1 mg terlipressin
acetate. In
other embodiments, the terlipressin dosage may be modified after a period of
time
administering the initial dose. In at least one example, the modified dosage
may be
about 2 mg terlipressin acetate.
[00145] In various embodiments, the injections may be administered
intravenously as slow bolus injections over 2 minutes, where the dose may be
repeated
every four to six hours. In one or more embodiments, the injections may be
administered to the patient over about four hours to about six hours as an IV
drip.
[00146] In an example, an initial terlipressin dosage is administered to the
patient in the range of about 0.5 mg to about 1.0 mg, every 4 to 6 hours, as a
series of
single doses, so that the patient receives a single dose in the range of about
0.5 mg to
about 1.0 mg of terlipressin followed by another single dose 4 to 6 hours
later. In
various embodiments, a patient may receive 4 to 6 doses over a 24 hour period,
where
each dose is in the range of about 0.5 mg to about 1.0 mg. In various
embodiments, the
total dosage does not exceed 4.0 mg over a 24 hour period. In some examples,
the
terlipressin dosage may be about 0.85 mg or about 1.0 mg terlipressin acetate.
[00147] At step 410, in some embodiments, a baseline serum creatinine level
may be measured before administration of terlipressin on day 1. Then, an
initial dose of
terlipressin may be administered to the patient with HRS-1. In an example, the
initial
dose of terlipressin may about 0.5 mg to about 1.0 mg, and it may be
administered
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every 6 hours for about 1-3 days. In at least one example, the initial dosage
may be
about 1.0 mg terlipressin acetate (i.e. 0.85 mg terlipressin).
[00148] At step 420, on day 4 1 day of administration (e.g. after a minimum
of
doses), the serum creatinine level may be assessed and compared to the
baseline
level. In various embodiments, the patient that is being administered the
terlipressin is
assessed at least once during the days 1 to 4 1 day of administration to
determine if
the patient is responding to the terlipressin. In various embodiments, the
patient may be
tested once at the end of 3 or 4 days of administration of the terlipressin.
In some
examples, the serum creatinine level may be continually assessed (e.g. daily)
until
administration is discontinued. In various embodiments, the dosage
administered to the
patient may be adjusted based upon the measured serum creatinine level(s). In
various
embodiments, a patient being administered terlipressin may have their serum
creatinine
levels monitored for the entire time period that the patient is receiving
terlipressin. In
one or more embodiments, the patient's serum creatinine level may be tested
every
day, or every other day, or every third day, or every fourth day, to confirm
that the
patient is still responding positively to the terlipressin treatment.
[00149] The serum creatinine levels may be measured by any of the methods
known in the art, for example, the Jaffe reaction using alkaline picrate. The
GFR may be
measured directly by clearance studies of exogenous markers, such as inulin,
iohexol,
iothalamate, and Cr51-EDTA, or by estimated glomerular filtration rate (eGFR)
using
creatinine testing methods that are traceable to a reference method based on
isotope
dilution-mass spectrometry (IDMS).
[00150] In various embodiments, the patient's creatinine levels are assessed
to
determine if there has been a reduction in the patient's serum creatinine,
where a
reduction in serum creatinine levels of about 1.0 mg/dL or greater, or in the
range of
about 1.0 mg/dL to about 2.0 mg/dL, or a reduction of about 1.7 mg/dL from the
patient's initial baseline value indicates an improvement in renal function
and that the
patient is responding to the terlipressin. In some examples, the assessed
serum
creatinine level may be 30% or more less than the baseline serum creatinine
level, may
be between 1% and 29% less than the baseline serum creatinine level, or may be
0% or
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greater than the baseline serum creatinine level. At steps 430, 440, and 450,
a modified
dosage of terlipressin may then be administered based on the comparison of the
assessed serum creatinine level at day 4 1 day and the baseline serum
creatinine
level.
[00151] At step 430, if the assessed SCr level decreased by 30% or more from
the baseline SCr level at day 4 1 day, the about 0.5 mg to about 1.0 mg
dosage of
terlipressin may be continued to be administered to the patient every 6 hours.
For
example, the modified dosage may be the same as the initial dosage (e.g. 0.5
mg to 1.0
mg) if the assessed SCr level decreased by 30% or more from the baseline SCr
level.
[00152] At step 440, if the assessed SCr level has decreased, but by less than
30% from the baseline level at day 4 1 day, the dosage of terlipressin may
be
increased to about 1.0 mg to about 2.0 mg every 6 hours. For example, the
modified
dosage may be about 0.1 mg to about 2.0 mg of terlipressin every 6 hours ( 30
min) (8
mg/day) if the assessed SCr level has decreased, but by less than 30% from the
baseline level. In at least one example, the modified dosage may be The
assessed
dose may not be increased from the initial dose if the subject had coronary
artery
disease; or in the clinical setting of circulatory overload, pulmonary edema,
or
treatment-refractory bronchospasm. In various embodiments, if dosing was
interrupted
due to a non-ischemic adverse event, terlipressin may be restarted at the same
or lower
dose (i.e., 0.5 to 1 mg q6h).
[00153] At step 450, if the assessed SCr level is at or above the baseline SCr
level at day 4 1 day, the administration of terlipressin may be
discontinued. For
example, the modified dosage may be a discontinuation of administering
terlipressin if
the assessed SCr level is at or above the baseline SCr level.
[00154] At step 460, administration of terlipressin may be continued until 24
hours after the patient achieves a second consecutive serum creatinine value
of 1.5
mg/dL at least 2 hours apart or for a maximum of 14 days. In various
embodiments, the
dosage may be repeated every four to six hours for a time period of one or
more days
until the patient shows recovery, or until the patient no longer shows
improvement. In
various embodiments, the duration of treatment of a patient with terlipressin
may be 1 to
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14 days. In various embodiments, the terlipressin may be administered for at
least 4
days. In various embodiments, the patient is administered terlipressin for up
to 14 days
unless the patient experiences an adverse event. In various embodiments, the
terlipressin may be administered for at least 3 days, at least 4 days, at
least 5 days, at
least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10
days, at least
11 days, at least 12 days, at least 13 days, or at least 14 days. In some
examples, the
terlipressin may be administered to the patient for a time period in the range
of about 2
days to about 14 days, or for a time period in the range of about 4 days to
about 8 days.
In various embodiments, the time period is in the range of about 7 days. In
various
embodiments, the terlipressin treatment may be continued until there is a
complete
response.
[00155] In one or more embodiments, a treatment protocol comprising dosages
of terlipressin surprisingly provides reversal of one or more complicating
factors, such
as vasodilation, and reduces mortality from the associated complications
within a 90
day window starting with treatment.
[00156] Treatment of the patient may include an improvement in renal function.
An improvement in renal function is indicated by a reduction in SCr of at
least 25% or
30% from baseline, reversal of HRS (defined as a decrease in SCr level to '1.5
mg/di),
and/or confirmed HRS reversal (defined as two serum creatinine values of 1.5
mg/dL
at least 48 hours apart)).
[00157] In one or more embodiments, the patent is alive at day 90 after
initiating terlipressin treatment. For example, a patient that experiences HRS
reversal,
verified HRS reversal, and/or greater than 30% improvement in SCr after
receiving
terlipressin may have at least a 60%, 65%, or 70% likelihood of being alive at
day 90.
In other embodiments, the patient is alive at day 90 post-liver transplant
after initiating
terlipressin treatment. For example, a patient that experiences HRS reversal,
verified
HRS reversal, and/or greater than 30% improvement in SCr after receiving
terlipressin
may have at least a 35%, 40%, or 45% likelihood of being alive at day 90.
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[00158] In various embodiments, the adult patient with HRS-1 also is SIRS
positive. In one or more embodiments, a patient with uncontrolled infection,
sepsis, or
septic shock is excluded from the terlipressin treatment.
[00159] In one or more embodiments, the patient is also up to a maximum of
100 g per day of albumin each day that the patient is treated with
terlipressin. In some
examples, the patient may continue to be administered albumin after
terlipressin has
been discontinued.
[00160] The percentage of patients who may achieve verified HRS reversal
may be significantly higher with terlipressin than with placebo. In some
examples, the
patients administered terlipressin may achieve two consecutive SCr values of
1.5 mg/dL
or less at least 2 hours apart while receiving treatment by day 14 or
discharge. This
demonstrates a robust and clinically significant improvement in renal
function. In
additional examples, the patients administered terlipressin may achieve an
absence of
renal replacement therapy (RRT) for at least 10 days, which emphasizes the
durability
of this improvement in renal function. The durability of HRS reversal with
terlipressin
may also persist to at least day 30 without the need for RRT. In other
examples, the
patient administered terlipressin may achieve survival for at least 10 days,
which
establishes the effect of treatment on a key clinical outcome of initial
survival.
Terlipressin may be superior to placebo in inducing a response across all
levels of
baseline SCr, with the response rate to terlipressin inversely related to the
baseline SCr.
[00161] Renal replacement therapy poses particular challenges to patients with
HRS-1 and advanced acute-on-chronic liver failure, and the lower rate of RRT
and
longer survival without RRT in the terlipressin group is clinically relevant.
This
significantly reduced need for RRT extending into the post-transplant period
in the
terlipressin group has important clinical implications, as post-transplant RRT
is a
significant predictor of post-transplant morbidity with worse graft survival
mortality, and
resource utilization.
[00162] In additional aspects of the disclosure, a method of increasing
survival
of a patient having HRS-1 and low MAP includes administering an effective dose
of
terlipressin to a patient in need thereof about every 6 hours by intravenous
(IV) bolus
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injection over about 2 minutes, where the dose is sufficient to yield an
increase in MAP
and decrease in heart rate in the patient.
[00163] In other aspects of the disclosure, a method of increasing survival of
a
patient having HRS-1 includes administering an effective dose of terlipressin
to a patient
in need thereof about every 6 hours by intravenous (IV) bolus injection over
about 2
minutes, where the dose is sufficient to yield an increase in the diastolic,
systolic and
MAP, and decrease in heart rate in the patient. In further aspects of the
disclosure, a
method of increasing survival of a patient having HRS-1 includes administering
an
effective dose of about 0.5 mg to about 2 mg terlipressin acetate to a patient
in need
thereof about every 4 to 10 hours by intravenous (IV) bolus injection over
about 1 to 5
minutes, where the dose is sufficient to yield an increase in MAP and decrease
in heart
rate in the patient.
[00164] Terlipressin may cause adverse effects generally consistent with its
mechanism of action (MOA) and class effects with the possibility of an
increased risk of
certain serious adverse event. Patient selection is extremely important when
employing
terlipressin. Efficacy and safety outcomes in patients with a serum creatinine
mg/dL
and/or a model end stage liver disease (MELD) score 35 at the time of
terlipressin
initiation may be a tipping point for clinical outcomes. For example, SCr 5
mg/dL,
MELD score 35, and/or acute-on-chronic liver failure (ACLF) Grade 3 may be a
threshold of advanced disease presentation, decreased kidney function
response, and
increased adverse events. Clinicians may consider avoiding terlipressin in
late-
presenting HRS-1 or in advanced acute on chronic liver failure, where the
likelihood of
benefit is low. Use of terlipressin in patients with SCr 5 mg/dL may be
considered only
when the anticipated benefit to the patient outweighs the potential risk. In
other
embodiments, use of terlipressin in patients with at least about SCr 5 mg/dL
may be
considered only when the anticipated benefit to the patient outweighs the
potential risk.
The adverse events may include ischemic or respiratory symptoms that may lead
to
serious or fatal outcomes. For example, one of the possible respiratory
symptoms is
serious respiratory failure, which may be a major safety concern. In one
embodiment,
the risk of respiratory failure may not be reliably predicted and managed.
There may be
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multiple potential causes of respiratory failure. Other adverse events may be
ischemia,
pneumonia, or sepsis without a clear mechanism. The risk of fluid overload and
associated albumin use may complicate the clinical presentation and management
of
the event.
[00165] The management of adverse events, side effects, and undesirable
symptoms for the current invention may include a variety of mitigation
strategies. In one
embodiment, the method of the present invention comprises the mitigation
strategy of
actively managing fluid overload during therapy. Actively managing fluid
overload may
comprise reducing or discontinuing the administration of albumin, other
fluids, and/or
judicious use of diuretics. For clarity, reducing the administration of
albumin may
comprise lowering the dose or interrupting the dose of albumin. If fluid
overload
persists, the method of treating may further comprise reducing or
discontinuing
terlipressin treatment. Management of fluid overload by reducing or
discontinuing the
administration of albumin, other fluids, and/or judicious use of diuretics may
also occur
wherein the patient additionally has respiratory failure, severe kidney
disease,
pulmonary edema, dyspnea, tachypnea, ischemia, or a combination thereof.
[00166] Actively managing fluid overload may comprise terlipressin dose
alteration, for example, if symptoms persist. Actively managing fluid overload
may also
comprise terlipressin dose reduction, dose interruption, or dose
discontinuation (i.e.,
treatment discontinuation), if symptoms, side effects, or adverse events
persist. In
another embodiment, the method of the present invention comprises the
mitigation
strategy of monitoring oxygen saturation during therapy. Monitoring oxygen
saturation
via pulse oximetry may identify patients at risk of developing serious
respiratory adverse
events.
[00167] Patients with acute-on-chronic liver failure (ACLF) Grade 3 and/or
serum creatinine 5 mg/dl treated according to the currently claimed invention
may be
at significant risk for serious or fatal respiratory failure. In one
embodiment, a mitigation
strategy may be to stop or discontinue treatment in patients with serum
creatinine 5
mg/di or patients with ACLF Grade 3. Another mitigation strategy in the
present
invention is to stop or discontinue treatment in patients with a hepatic
encephalopathy
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score 3. Another mitigation strategy to use in the present invention is to
exclude from
treatment (i.e., exclusion criteria) patients with serum creatinine 5 mg/dl or
a hepatic
encephalopathy score 3, and/or an ACLF Grade 3. Stated differently, the
present
invention also includes an embodiment where only patients are treated (i.e.,
inclusion
criteria) if they have a serum creatinine < 5 mg/di, or a hepatic
encephalopathy score <
3, and/or an ACLF Grade < 3. In some embodiments, terlipressin may be
administered
to a patient with less than a critical level or threshold level of serum
creatinine. In some
examples, the critical level or threshold level may be about 5 mg/c11. In at
least one
example, terlipressin may be administered to a patient if the patient has a
serum
creatinine level of < 5 mg/d1.
[00168] In some embodiments, the duration of terlipressin treatment may be
about 6 days to about 7 days in patients with presenting SCr <5 mg/dL as
compared to
about 6 days to about 11 days in patients with a presenting SCr L= 5 mg/dL and
treated
with terlipressin. There may be no significant difference between the groups
in the
proportion of patients who receive antibiotics or albumin.
[00169] In additional embodiments, a patient with a serum creatinine level of
<
mg/dl and administered a dose of terlipressin may have a decreased likelihood
of
adverse events, an increased overall survival, a decreased overall ICU, non-
ICU, or
hospital stay, increased likelihood of complete response, and/or an increased
likelihood
of a partial response as compared to a patient with a serum creatinine level
of 5 mg/di
administered terlipressin. A complete response may be when the patient's SCr
level has
decreased to mg/dl. In some examples, terlipressin may be
continued to be
administered to the patient until the patient's serum creatinine level is
mg/c11. In
other examples, terlipressin may be continued to be administered to the
patient until 24
hours after two consecutive measured SCr levels of
mg/dl at least 2 hours apart. A
partial response may be when the patient's SCr level has decreased 20%, or
preferably > 30%, but is >1.5 mg/dL. In an example, terlipressin may be
continued to be
administered to the patient until the patient's serum creatinine level has
improved by
greater than 20%.
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[00170] Higher presenting SCr may be linked to poorer efficacy in patients
with
HRS-1. For example, patients with SCr mg/dL may be significantly more
likely to
develop adverse events compared to those with a presenting SCr <5 mg/dL when
administered terlipressin. In some examples, a complete response may be
achieved in
about 50% to about 60% of patients with presenting SCr <5 mg/dL as compared to
about 10% to about 20% in patients with presenting SCr mg/dL when
administered
terlipressin. In other examples, a partial response may be achieved in about
50% to
about 60% of patients with presenting SCr <5 mg/dL as compared to about 15% to
about 25% in patients with presenting SCr mg/dL when administered
terlipressin. In
additional examples, patients with presenting SCr 5 mg/dL may be more likely
to
develop fluid overload or pulmonary edema (about 20% to about 30%) and multi-
organ
failure (about 25% to about 35%) compared to patients with a SCr <5 mg/dL
(about 10%
to about 20% and about 5% to about 10%, respectively) when administered
terlipressin.
Overall survival may be significantly better in patients with presenting SCr
<5 mg/dL
than in patients with presenting SCr
mg/dL when administered terlipressin. In further
examples, patients with SCr <5 may have a significantly shorter ICU stay of
about 0.5 to
about 1.5 days as compared to about 5 days to about 10 days for patients with
presenting SCr mg/dL when administered terlipressin. In yet further
examples,
patients with SCr <5 may have a significantly shorter non-ICU stay of about 20
days to
about 25 days as compared to about 30 days to about 40 days for patients with
presenting SCr mg/dL when administered terlipressin. In even further
examples,
patients with SCr <5 may have a significantly shorter total length of hospital
stay of
about 20 days to about 25 days as compared to about 40 days to about 45 days
for
patients with presenting SCr mg/dL when administered terlipressin.
[00171] A further mitigation strategy in the present invention is to stabilize
patients with respiratory events. Among other factors, the present invention
may further
comprise managing fluid overload and pneumonia prior to treatment. The
mitigation
strategies that may be used as part of the present invention may result in
reduced
adverse events, a reduced risk of mortality, a reduced incidence of mortality,
and
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combinations thereof. Reduced risk of mortality or reduced incidence of
mortality may
include overall survival (e.g., measured as alive at Day 90 after beginning
treatment).
[00172] Higher baseline MELD scores may be linked to poorer efficacy (e.g.
poor survival) in patients with HRS-1. For example, patients with a baseline
MELD
score of greater than 35 may be significantly more likely to develop adverse
events
compared to those with a baseline MELD score of less than 35 when administered
terlipressin. Patients may be excluded from treatment if the patient is listed
for liver
transplant with a MELD score
[00173] In some embodiments, provided herein is a method of treating a
patient with HRS-1 by administering a dose of terlipressin to the patient by
IV injection
when the patient has a baseline model end stage liver disease (MELD) score of
less
than 35. In some examples, the patient is listed for transplant at baseline
and has a
baseline MELD <35. In other examples, the patient is not listed for transplant
at
baseline and has MELD score < 35 or 35. The administration of terlipressin to
this
subset of patients may lead to increasing overall survival of the patient,
decreasing an
overall ICU or hospital stay of the patient, increasing a complete response of
the
patient, and/or increasing a partial response of the patient. In some
embodiments, the
overall survival at day 90 of a patient with a baseline MELD score <35 treated
with
terlipressin may be increased by about 5% to 50%, about 5% to 15%, about 10%
to
20%, about 25% to 35%, about 30% to 40%, about 35% to 45%, or about 40% to 50%
as compared to placebo and/or as compared to a patient with a baseline MELD
score
35 treated with terlipressin. In some embodiments, the transplant-free
survival at day 90
of the patient with a baseline MELD score <35 treated with terlipressin may be
increased by about 5% to 50%, about 5% to 15%, about 10% to 20%, about 25% to
35%, about 30% to 40%, about 35% to 45%, or about 40% to 50% as compared to
placebo and/or as compared to a patient with a baseline MELD score 35 treated
with
terlipressin.
[00174] In some embodiments, the patient with a MELD score < 35 may also
have severe kidney disease, pulmonary edema, dyspnea, or a combination
thereof.
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[00175] The method may further include acquiring the baseline MELD score of
the patient, acquiring a serum creatinine (SCr) level in the patient prior to
administering
the dose of terlipressin to determine a baseline SCr level, and/or determining
the
patient's acute-on-chronic liver failure (ACLF) grade. In some embodiments,
the
terlipressin may not be administered if the baseline SCr is 5 mg/dland/or ACLF
Grade
is 3. In other embodiments, the method may include discontinuing
administration or
reducing the dose of terlipressin in patients with SCr 5 mg/dl and/or an ACLF
Grade
3. In additional embodiments, a dose of terlipressin may be administered to
the patient if
the patient's baseline MELD score is < 35 and the baseline SCr level is < 5
mg/c11.
Patients with a baseline MELD score of less than 35 may further be monitored
for a SCr
level of greater than 5 mg/dl and or an ACLF grade of greater than or equal to
3 for
discontinuation of the terlipressin administration. In some examples, the
patient is listed
for transplant at baseline and has a baseline MELD <35. In other examples, the
patient
is not listed for transplant at baseline and has MELD score < 35 or 35.
[00176] In some embodiments, administering terlipressin to patients with a
baseline MELD score of < 35 may decrease the patient's risk of mortality (i.e.
increase
survival). The patient may be listed for transplant and have a MELD score of <
35. In an
embodiment, treatment of patients on the transplant list at baseline with a
baseline
MELD score of < 35 may further aid in not compromising a patient's place on a
transplant list. In some embodiments, the patient may have a reduced risk of
their place
on a transplant list being compromised or impacted due to the administration
of
terlipressin.
[00177] Only patients who are actively listed for transplantation can receive
an
available organ. Their wait time from being listed to receiving a liver
transplant is
dependent on other factors (i.e., MELD score, geographic region, blood type)
and may
vary from days to months based on their MELD score. Excluding patients who are
likely
to receive a transplant during or shortly after terlipressin treatment may
reduce the risk
that such patients will not receive a transplant due to any adverse effects of
terlipressin
therapy, e.g., respiratory failure. This also prioritizes patients who are at
highest risk of
dying while waiting for a liver and therefore directs livers to those most in
need.
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[00178] For example, a patient on the transplant list with a MELD score of 35
may be high on the transplant list and therefore may have a faster treatment
time by
waiting for the liver transplant rather than be treated with terlipressin.
Therefore, not
treating patients listed for a liver transplant with a baseline MELD score 35
may allow
the patient to maintain their spot on the transplant list and receive a
transplant quicker
than if they were first treated with terlipressin. In at least one embodiment,
the patient
may only be treated if the patient belongs to a patient population that has
median
waiting time from listing to transplant of about 5.6 months or greater. In
another
embodiment, the patient may be excluded from treatment if the patient belongs
to a
patient population that has median waiting time from listing to transplant of
0.23 months
(approximately 7 days) or less. In additional embodiments, the patient's ICU
stay, non-
ICU stay, and/or total length of hospital stay may be shortened due to the
patient having
a baseline MELD score < 35, a baseline SCr level of < 5 mg/di, and/or an SCLF
grade
of <3.
[00179] In some embodiments, the terlipressin administration is continued
until
there is a complete response or a partial response. In some embodiments,
discontinuing administration or reducing the dose of terlipressin occurs in
patients with
respiratory failure. For example, administering terlipressin to patients with
a baseline
MELD score of < 35 may reduce the likelihood of the patient having respiratory
failure
as compared to patients with a baseline MELD score of 35.
[00180] The dose of terlipressin administered may be 0.5 mg to about 2 mg
terlipressin acetate and may be administered every 4 to 10 hours by IV bolus
injection
over about 1 to 5 minutes. In at least one example, the terlipressin may be
administered
every 6 hours by IV bolus injection over 2 minutes.
[00181] In some embodiments, the method may further include monitoring the
patient's oxygen saturation during treatment with the terlipressin. The
monitoring of the
oxygen saturation may decrease the occurrence of adverse events. For example,
a
method of treating an HRS patient may include obtaining a baseline oxygenation
level
(Sp02) via pulse oximetry, administering a dose of terlipressin to the patient
by IV
injection if the patient is not experiencing hypoxia, and monitoring the
patient's Sp02
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during treatment with the terlipressin. The patient's Sp02 may be obtained at
baseline
prior to the first dose of terlipressin and then may be monitored at least 3
times a day, at
least 4 times a day, at least 5 times a day, at least 6 times a day, or
continuously during
administration of terlipressin. The patient's oxygen saturation (Sp02) may be
monitored
for hypoxia. An Sp02 value of <90% may be indicative of some degree of
hypoxia.
Fraction of inspired oxygen (Fi02) may also be monitored as an indication of
pulmonary
function. In an example, Fi02 0.36 may be an indication of compromised
pulmonary
function. In an embodiment, the method may further include discontinuing
administration or reducing the dose of terlipressin if hypoxia is detected.
[00182] In additional embodiments, the method may further include monitoring
the patient for fluid overload during treatment with the terlipressin. The
terlipressin dose
may then be reduced or discontinued if fluid overload develops. Diuretics may
also be
administered to the patient if fluid overload develops.
[00183] In an embodiment, the method may further include measuring the SCr
level in the patient during administration of terlipressin. The administration
may then be
continued until the patient's SCr level is mg/dl or until the patient
experiences
greater than 20% improvement in SCr. In some examples, administration is
continued
until the patient experiences greater than 30% improvement in serum
creatinine.
[00184] Also provided herein is a method of treating a patient with HRS-1 by
narrowing the population of eligible patients for treatment to a mitigated
population to
reduce the risks selected from the group consisting of respiratory failure,
serious
adverse events, death, and combinations thereof and then administering a dose
of
terlipressin to the patient of the mitigated population by IV injection. The
mitigated
population excludes patients with baseline ACLF Grade 3, baseline serum
creatinine
mg/dL, and/or patients listed for transplant at baseline with a baseline MELD
It was
surprising that this mitigated population had improved survival, lower
incidence of
respiratory failure, and lower pre-transplant mortality as compared to an
overall
population treated with terlipressin. The treatment of HRS-1 patients having a
baseline
ACLF Grade 0-2, baseline SCr <5 nrig/dL, and/or be listed for transplant at
baseline with
a baseline MELD <35 may favorably impact the incidence of liver
transplantation and
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minimize the risk that a patient listed for liver transplant will be precluded
from receiving
a transplant due to a potential adverse effect of terlipressin.
[00185] Treating this subset of HRS patients (e.g. mitigated population) leads
to a higher rate of verified HRS reversal, lower incidence of renal
replacement therapy
(RRT), and favorable RRT-free survival with terlipressin compared with
placebo. For
example, this subset of treated patients may have a reduction in risks
compared with
the overall population, including lower incidence of respiratory failure,
overall mortality,
and pre-transplant mortality. In some embodiments, the overall survival,
verified HRS
reversal, HRS reversal, durability of HRS reversal, HRS reversal in SIRS
subgroup,
and/or verified HRS reversal without HRS recurrence by day 30 of a patient in
the
mitigated population treated with terlipressin may be increased by about 5% to
50%,
including about 5% to 15%, about 10% to 20%, about 25% to 35%, or about 30% to
40% as compared to the overall population treated with terlipressin. In other
embodiments, the overall survival, verified HRS reversal, HRS reversal,
durability of
HRS reversal, HRS reversal in SIRS subgroup, and/or verified HRS reversal
without
HRS recurrence by day 30 of a patient in the mitigated population treated with
terlipressin may be increased by about 5% to 100%, including about 5% to 15%,
about
10% to 20%, about 25% to 35%, about 30% to 40%, about 35% to 45%, about 40% to
50%, about 50% to 60%, about 60% to 70%, about 70% to 80%, about 80% to 90%,
or
90% to 100% as compared to the overall population or the mitigated population
given
placebo. In additional embodiments, there may be an about 5% to 50%, about 5%
to
15%, about 10% to 20%, about 25% to 35%, about 30% to 40%, about 35% to 45%,
or
about 40% to 50% decrease in the incidence of RRT for patients alive by day 90
for
patients in the mitigated population treated with terlipressin as compared to
the overall
population or mitigated population given placebo. In various embodiments,
patients in
the mitigated population treated with terlipressin may have an increased
likelihood of
survival without RRT by day 14, day 30, or day 60 as compared to patients in
the overall
population treated with terlipressin. For example, patients in the mitigated
population
treated with terlipressin may have an about 2% to about 20%, about 5% to 15%,
or
about 10% to 20% increase in the likelihood of survival without RRT by day 14,
day 30,
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or day 60 as compared to patients in the overall population treated with
terlipressin. In
further embodiments, patients in the mitigated population treated with
terlipressin may
have an increased likelihood of survival without RRT by day 14, day 30, day
60, or day
90 as compared to patients in the overall population treated with placebo or
the
mitigated population treated with placebo. For example, patients in the
mitigated
population treated with terlipressin may have an about 2% to about 40%, about
5% to
10%, about 10% to 20%, about 20% to 30%, or about 30% to 40% increase in the
likelihood of survival without RRT by day 14, day 30, day 60, or day 90 as
compared to
patients in the overall population treated with placebo or the mitigated
population
treated with placebo.
EXAMPLES
Example 1:
[00186] A randomized, placebo-controlled, double-blind study ("REVERSE")
was conducted to evaluate the efficacy of terlipressin in HRS type 1. The
objective of
the study was to determine the efficacy and safety of intravenous terlipressin
compared
with placebo in the treatment of adult patients with HRS type1 receiving
intravenous
albumin. Men and women aged 18 years or older having cirrhosis, ascites, and a
diagnosis of HRS type 1 based on the 2007 International Club of Ascites (ICA)
diagnostic criteria (Salerno F, Gerbes A, Gines P, Wong F, Arroyo V.,
Diagnosis,
prevention and treatment of hepatorenal syndrome in cirrhosis, Gut. 2007;
56:1310-
1318) were eligible for participation. Patients with an SCr level>2.5 mg/dL
and either a
doubling of SCr within 2 weeks or a change in SCr levels over time indicating
a
trajectory with a slope equal to or greater than that of a doubling within 2
weeks were
enrolled.
[00187] Exclusion criteria were intended to product a patient sample limited
to
individuals with functional renal impairment secondary to cirrhosis and
ascites, who
could safely be administered terlipressin and who could be expected to survive
through
the active study period. Among the original exclusion criteria was an
exclusion criterion
for patients with systemic inflammatory response syndrome (SIRS), defined as
the
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presence of 2 or more of the following findings: (1) temperature>38 C. or <36
C.; (2)
heart rate>90/m in; (3) respiratory rate of >20/m in or a PaCO2 of <32 mm Hg;
(4) white
blood cell count of >12,000 cells/pL or <4,000/g L. This was based on the
concern of
enrolling patients with uncontrolled infection. However, it was also
recognized that
patients with decompensated liver disease frequently have SIRS criteria in the
absence
of uncontrolled infection or sepsis, and that the presence of 2 or more SIRS
criteria is
associated with a poor prognosis (Thabut, et al., "Model for End-Stage Liver
Disease
Score and Systemic Inflammatory Response Are Major Prognostic Factors in
Patients
with Cirrhosis and Acute Functional Renal Failure," HEPATOLOGY, Vol. 46, No.
6,
December 2007, pp. 1872-1882). Furthermore, the IAC criteria for the
definition of HRS
type 1 allows for patients with ongoing bacterial infection, but not sepsis or
uncontrolled
infection, to be considered as having HRS type 1 (as opposed to renal
dysfunction
associated with infection) (Salerno F, Gerbes A, Gines P, Wong F, Arroyo V.,
Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis, Gut.
2007;
56:1310-1318). The trial protocol required 2 days of anti-infective therapy
for
documented or suspected infection, allowing enrollment where any SIRS criteria
were
felt to be most likely explained by underlying hepatic decompensation or other
non-
infection clinical circumstances. Patients with overt sepsis, septic shock, or
uncontrolled
infection were excluded. This approach was felt to minimize the chances of
enrolling
patients at high risk for serious infection while not unduly restricting the
enrollment of
subjects with HRS type 1.
[00188] The patients selected for treatment clinically met the criteria for
HRS
type 1, where ICA criteria for HRS type 1 allows for patients with ongoing
bacterial
infection, but not sepsis, to be considered as having HRS type 1, as opposed
to renal
dysfunction associated with infection. A diagnosis of HRS was not made where
the
patient remained with obvious manifestations of uncontrolled infection despite
antibiotic
treatment.
[00189] During the active study period treatment with the blinded study drug
continued until at least two SCr values<1.5 mg/dL were obtained at least 48
hours
apart, or up to 14 days. Duration of treatment was allowed to extend to a
maximum of
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15 or 16 days if HRS reversal was first achieved on days 13 or 14,
respectively.
Patients in the active treatment group received terlipressin 1 mg
intravenously every 6
hours as a slow bolus injection over 2 minutes. Criteria for dose increases,
study
discontinuation, treatment resumption and treatment completion during the
active study
period were provided for. The dosing regimen for patients in the placebo (6 m
L
lyophilized mannitol solution) group was identical to the terlipressin
regimen. The follow-
up period began after the end of study treatment and concluded 90 days after
the start
of study treatment. Survival, renal replacement therapy, and transplantation
were
assessed.
[00190] The SIRS subgroup of patients in this study was defined as any
subject with 2 of 3 criteria available from the study database which included:
(1)
WBC<4 or >12 cells/pL; (2) HR>90 bpm and (3) HCO3<21 mmol/L. The latter
criterion
represented an approximation of the SIRS criterion PaCO2 of <32 mm Hg. This
approximation was derived from the observed HCO3 in subjects with HRS in whom
a
PaCO2 value was available and the calculated HCO3 in subjects with
decompensated
liver disease and PaCO2 of <32 mm Hg. The non-SIRS subgroup was defined as
subjects with <2 criteria described above. Terlipressin response was analyzed
in the
SIRS and non-SIRS subgroups to determine whether SIRS status had any effect on
terlipressin efficacy.
[00191] A total of 196 patients were enrolled in the study. Of the 196
patients
enrolled, 58 were initially identified as having 2 SIRS criteria, including
WBC<4 or >12
cells/pL, HR>90 bpm, and HCO3<21 mmol/L, wherein this population was
identified as
the SIRS subgroup. Based on the criteria defining the SIRS subgroup, baseline
WBC
and heart rate were slightly higher, and bicarbonate slightly lower, in the
SIRS subgroup
compared to the non-SIRS and overall study populations. The results of the
analysis are
shown in FIG. 3.
[00192] It was also recognized that patients with decompensated liver disease
frequently have SIRS criteria in the absence of uncontrolled infection or
sepsis, and that
the presence of two or more SIRS criteria is associated with a poor prognosis.
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[00193] In one or more embodiments, reversal of HRS is indicated by a
decrease in SCr level to 1.5 mg/di, and confirmed reversal of HRS is defined
as two
SCr values of mg/dL at least 48 hours apart.
[00194] As shown in FIG. 3, patients identified as having HRS-1 and at least
two of the three criteria for SIRS on a terlipressin treatment protocol
exhibited a
statistically significant increase in confirmed reversal of HRS (32.1% vs.
3.3%,
p<0.005), HRS reversal (42.9% vs. 6.7%, p<0.002) and renal function (change
from
baseline in SCr, mg/dL, -1.7 vs. -0.5, p<0.0001) compared to placebo. In
contrast, in
the group of patients having HRS-1 and fewer than two of the SIRS criteria,
confirmed
reversal of HRS vs. placebo was 14.5% vs. 17.4%, HRS reversal vs. placebo was
15.9% vs. 18.8%, and renal function change vs. placebo was -0.8 vs. -0.7
mg/dL.
These results indicate that the presence of two or more of the SIRS criteria
indicates
that the patient is more likely to have a positive response to treatment with
terlipressin.
[00195] In addition, in the treatment groups, patients with HRS-1 and two or
more SIRS criteria showed an overall survival rate comparable to patients that
were
suffering from HRS-1, but did not have at least two of the three criteria for
SIRS (57.1%
vs. 58%).
Example 2:
[00196] A randomized, placebo-controlled, double-blind study ("CONFIRM")
was conducted to evaluate the efficacy of terlipressin in HRS type 1. The
objective of
the study was to characterize the efficacy and safety of terlipressin plus
albumin versus
albumin alone for the treatment of HRS-1 in patients with well-defined HRS-1.
The study
used the similar inclusion and exclusion criteria as described in Example 1.
[00197] In particular, HRS-1 was defined based on modified prior criteria
outlined by the International Club of Ascites (ICA), as rapidly deteriorating
renal function
to SCr 2.25 mg/dL, with actual or projected doubling of SCr within 2 weeks,
without
improvement in renal function (<20% decrease in SCr 48 hours after both
diuretic
withdrawal and albumin-fluid challenge) in adult patients with cirrhosis and
ascites.
Subjects were randomized 2:1 to terlipressin (1 mg IV every 6 hours) or
placebo, plus
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albumin in both groups. Treatment was continued to Day 14 unless the following
occurred: verified HRS reversal (VHRSR), renal replacement therapy (RRT),
liver
transplantation (LT) or SCr at or above baseline (BL) at Day 4. VHRSR, the
primary
endpoint, was defined as 2 consecutive SCr values 1.5 mg/dL, at least 2 hours
apart,
with subjects alive without RRT for at least 10 days after the second SCr
mg/dL;
HRS reversal (HRSR) was a decrease in SCr to 1.5 mg/dL. Secondary end points
included HRS reversal (any SCr value 1.5 mg/dL or less during treatment), HRS
reversal without RRT by day 30, HRS reversal in patients with systemic
inflammatory
response syndrome, and verified HRS reversal without recurrence by day 30.
[00198] The patients were at least 18 years of age, with cirrhosis, ascites,
and
rapidly progressive renal failure, with a SCr doubling to at least 2.25 mg/dL
within 14
days. Major exclusion criteria included SCr of greater than 7.0 mg/dL, one or
more
large-volume paracenteses of 4 L or more within 2 days of randomization,
evidence of
parenchymal renal diseases or obstructive uropathy, or presence of sepsis
and/or
uncontrolled bacterial infection. Patients with severe cardiovascular disease
or recent
(within 4 weeks) renal replacement therapy (RRT) were excluded.
[00199] 300 subjects were enrolled in the study. Of the 300 subjects, 199 were
randomized to terlipressin and 101 to placebo (albumin alone). Patients were
stratified
by qualifying SCr (less than 3.4 mg/dL or 3.4 mg/dL or greater) and pre-
enrollment
large-volume paracentesis (at least one single event of 4 L or greater, or
less than 4 L
within 3 to 14 days prior to randomization). Concomitant albumin was
administered in
82.9% of patients in the terlipressin group (165 of 199; mean [SD] total dose
of 199.4
[146.8] g) versus 91.1% (92 of 101; mean [SD] dose of 239.5 [183.6] g) in the
placebo
group (P=0.06). One hundred forty-five patients (72.9%) in the terlipressin
group and 72
(71.3%) in the placebo group had received prior midodrine and octreotide.
[00200] Demographic and BL clinical characteristics were similar between
treatment groups. For example, the two treatment groups had similar average
age,
weight, height, sex distribution, ethnicity distribution, race distribution,
presence of
alcoholic hepatitis, baseline serum creatinine, large volume paracentesis
(LVP)
randomization strata, baseline model end stage liver disease (MELD) score,
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Child-Pugh score, baseline white blood cell count, baseline bilirubin,
baseline mean
arterial pressure (MAP), baseline heart rate, baseline blood urea nitrogen
(BUN),
baseline bicarbonate (HCO3) or carbon Dioxide (CO2), baseline temperature,
baseline
respiratory rate, baseline acute on chronic liver failure (ACLF) grade,
baseline chronic
liver failure-sepsis organ failure assessment (CLIF-SOFA) score and presence
of prior
conditions/treatments such as esophageal variceal hemorrhage (EVH) banding,
pneumonia, urinary tract infection (UTI), spontaneous bacterial peritonitis
(SBP), and
receipt of albumin. The proportion of patients in each group who underwent LT
was
23.1% for terlipressin and 28.7% for placebo.
[00201] A baseline SCr value was assessed before the patients received the
assigned treatment. Patients received blinded assigned treatment (terlipressin
or
placebo) 1 mg administered intravenously over 2 minutes every 6 hours ( 30
minutes).
In keeping with current guidelines, it was strongly recommended that albumin
(1 g/kg to
a maximum of 100 g, on day 1 and 20 to 40 g/day thereafter) be administered to
all
subjects. If SCr decreased <30% from the baseline value on Day 4, after a
minimum of
doses of study drug, dose increase to 2 mg every 6 hours ( 30 minutes) (8
mg/day)
was mandated, except in subjects with coronary artery disease or in the
setting of
circulatory overload, pulmonary edema, or bronchospasm. Dose resumption was
permitted after interruption for adverse events except for cardiac or
mesenteric
ischemia, for which treatment was permanently discontinued.
[00202] The primary efficacy end point was the incidence of verified HRS
reversal, defined as the percentage of patients with two consecutive SCr
values no
greater than 1.5 mg/dL at least 2 hours apart, while remaining alive without
RRT for at
least 10 days after achieving verified HRS reversal, while excluding SCr
values after
RRT, transjugular intrahepatic portosystemic shunt, liver transplant, or open-
label
vasopressor from primary end point analysis. 58 patients (29.1%) treated with
terlipressin achieved verified HRS reversal versus 16 (15.8%) treated with
placebo
(P=0.01).
[00203] Secondary efficacy end points included incidence of HRS reversal,
defined as the percentage of patients with an on-treatment SCr value of 1.5
mg/dL or
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less; durability of HRS reversal, defined as the percentage of patients with
HRS reversal
without RRT to day 30; incidence of HRS reversal among patients with systemic
inflammatory response syndrome; and incidence of verified HRS reversal without
HRS
recurrence by day 30. 36.2% of patients treated with terlipressin achieved HRS
reversal
versus 16.8%, (P<0.001) treated with placebo. 31.7% of patients treated with
terlipressin achieved HRS reversal without RRT by day 30 versus 15.8%
(P=0.003)
treated with placebo. The reduction in RRT requirement with terlipressin
appears to
extend into the post¨liver transplant period, with only 9 of 46 patients
(19.6%) requiring
RRT post-transplant, significantly less than what was observed in the placebo
group (13
of 29 patients or 44.8%), (P=0.04). A slightly lower percentage of patients in
the
terlipressin group received a liver transplant (23.1% [46 of 199]) compared
with placebo
(28.7% [29 of 101]). 24.1% of patients treated with terlipressin achieved
verified HRS
reversal without recurrence by day 30 versus 15.8%, (P=0.09) treated with
placebo.
[00204] 132/300 (44%) of subjects met systemic inflammatory response
syndrome (SIRS) criteria, as defined in Example 1. Patients with overt sepsis,
septic
shock, or uncontrolled infection were excluded. In the SIRS subgroup, 84
patients were
treated with terlipressin per the protocol in Example 1 and 48 patients were
give
albumin only (placebo).
[00205] Some baseline values of SIRS patients treated with terlipressin or
placebo are shown in Table 1 below.
Table 1.
SIRS Subgroup SIRS Subgroup
Terlipressin n=84 Placebo n=48
BL SCr 3.5 (0.98) 3.7 (1.06)
mg/dL(mean(SD)
(2.3-6.2) (2.2-6.1)
(range)
MELD mean (SD) 33.8 (6.27) 33.5 (6.74)
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CPT score mean (SD) 10.2 (1.82) 10.3 (2.26)
[00206] As seen in Table 2, 33.3% of patients with SIRS and treated with
terlipressin experienced HRS reversal, as compared to only 6.3% of the SIRS
patients
given placebo. In addition, 26.2% of patients with SIRS and treated with
terlipressin
experienced verified HRS reversal, as compared to only 4.2% of the SIRS
patients
given placebo.
Table 2.
SIRS Subgroup
(N = 132)
Terlipressin Placebo
(N = 84) (N = 48) P value
n(%) n(%)
HRS Reversal (n, %) 28 (33.3) 3 (6.3) <.001
95% Cl (0.2, 0.4) (0.0, 0.1)
Verified HRS Reversal 22 (26.2) 2 (4.2) <.001
[00207] Table 3 shows transplant-free survival up to 90 days for subjects with
HRS reversal and/or greater than 30% improvement in serum creatinine (SCr)
compared to subjects with no HRS reversal and no more than 30% improvement in
SCr
in the SIRS subgroup of the intent-to-treat population. 45.5% of the SIRS
subgroup
treated with terlipressin having HRS reversal and/or at least 30% improvement
in SCr
were alive and transplant-free at day 90, as compared to 28.6% for placebo.
72.7% of
the SIRS subgroup treated with terlipressin having HRS reversal and/or at
least 30%
improvement in SCr were alive at day 90, as compared to 57.1% for placebo.
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Table 3.
SIRS Subgroup:
HRS Reversal and/or Greater
than 30%
Improvement in SCr
Terlipressin Placebo
N Parameter N Parameter
Transplant-free Survival up to
90 Days
Survival Estimate 33 0.680 7 0.536
Alive and Transplant-free Day 90(n%) at
33 15 (45.5) 7 2
(28.6)
,
Overall Survival up to 90 Days
Survival Estimate 33 0.727 7 0.571
Alive at Day 90 (n, %) 33 24 (72.7) 7 4
(57.1)
[00208] A significantly higher proportion of subjects in the SIRS subgroup of
the intent-to-treat (ITT) population in the terlipressin group (33.3%) than in
the placebo
group (6.3%) achieved HRS reversal. Among subjects with SIRS at baseline, the
incidence of RRT was lower in the terlipressin group than in the placebo group
at all
follow-up timepoints (Table 4). The mean cumulative frequency of RRT through
Day 90
were 7.3 days in the terlipressin group compared to 15.2 days in the placebo
group.
Table 4. RRT in Subjects with SIRS at Baseline
Terlipressin (N=84) n (%) Placebo
(N=48) n (%)
Subjects with RRT by Day 14 20 (23.8) 20 (41.7)
Subjects with RRT by Day 30 23 (27.4) 21 (43.8)
Subjects with RRT by Day 60 25 (29.8) 22 (45.8)
Subjects with RRT by day 90 27 (32.1) 22 (45.8)
Cumulative Frequency of RRT
through Day 30
23 22
Mean (SD) 4.5 (3.63) 7.7
(6.56)
Cumulative Frequency of RRT
through Day 90
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27 22
Mean (SD) 7.3 (9.08)
15.2 (15.27)
[00209] The median time to first RRT was 6.0 days in the terlipressin group
and 5.5 days in the placebo group. The transplant-free survival estimate up to
Day 90
was higher in the terlipressin group than the placebo group for subjects with
SIRS at
baseline (Table 5).
Table 5. Transplant-free Survival up to 90 Days with Events for Death and
Transplant in
Subjects with SIRS at Baseline by Treatment Group (Intent-to-treat Population,
SIRS
Subgroup)
Terlipressin Placebo
Parameter N Parameter P-
value
Transplant-Free
Survival up to 90 Days
Survival Estimate 84 0.290 48 0.192
0.363
Median Days of 84 15.0 48 18.0
Survival
Alive and Transplant- 84 26 (31.0) 48 10 (20.8)
Free at Day 90 (n,%)
[00210] After Day 30, the overall survival estimate up to Day 90 was slightly
higher in the terlipressin group than the placebo group for subjects with SIRS
at
baseline. For the SIRS subgroup, overall survival of subjects out to 90 days
was
analyzed to compare differences between subjects who achieved verified HRS
reversal
or >30% improvement in serum creatinine and those who did not). For the SIRS
subgroup, in both treatment groups up to Day 90, the survival estimate was
higher in
responders than nonresponders. The RRT-free survival estimate up to Day 90 was
higher in the terlipressin group than the placebo group for subjects with SIRS
at
baseline.
[00211] A lower percentage of subjects with SIRS at baseline in the
terlipressin
group was admitted to the ICU: 14 (16.7%) subjects in the terlipressin group
compared
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with 12 (25.0%) subjects in the placebo group. SIRS subjects in the
terlipressin group
had a shorter mean length of stay in the ICU (6.3 days) than in the placebo
group (12.1
days).
[00212] Applying strict criteria defining HRS-1, the study demonstrated a
significant reversal of worsening renal function in cirrhotic patients treated
with
terlipressin plus albumin when compared to those treated with albumin alone,
including
patients with SIRS criteria. This response was durable and associated with
less need
for early RRT. Therefore, terlipressin is effective in improving renal
function and
achieving HRS reversal in patients with HRS-1 and progressive advanced liver
disease.
Example 3:
[00213] As seen in FIGS. 6A-6B, there was an increased incidence of
respiratory failure in those patients who received terlipressin, but not in
those who
received placebo. In FIG. 6B, the incidence of respiratory failure was based
on CLIF-
SOFA score definition of respiratory failure. Therefore, this study assessed
in patients
with HRS1 whether the presence of severe or grade 3 ACLF according to the EASL-
CLIF system at baseline was a risk factor for the development of respiratory
failure with
terlipressin use.
[00214] The study was a double-blind placebo-controlled trial. 300 patients
with
HRS-1 were randomized 2:1 to receive terlipressin versus placebo in 1-2mg iv.
bolus
injections 6 hourly, both with albumin. HRS-1 was defined as rapidly rising
serum
creatinine (SCr) to 2.25mg/dL in <14 days without response to volume challenge
or
evidence of structural renal disease.
[00215] All patients were assessed for organ failure (OF) per EASL-CLIF
criteria and then classified into grades of acute-on-chronic liver failure
(ACLF). All
patients had at minimum grade 1 ACLF due to the presence of HRS-1; grades 2
and 3
ACLF represent 2 or 3 OFs respectively. Patients were separated into into
grade 2
and grade 3 ACLF subgroups. The effects of terlipressin vs. placebo on the
incidence of
RF between these subgroups were compared. Table 6 shows the patient
demographics
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and Table 7 shows the baseline clinical and laboratory parameters in the
patients of the
study.
Table 6. Patient Demographics
ACLF Grade 52 (n=242) ACLF Grade 3
(n=58)
Terlipressin Placebo Terlipressin Placebo
159 83 40 18
Age (yrs) 55.7 11.0 54.6 11.7 47.6 10.8 47.8
10.8
M:F (n) 94:66 48:33 26:14 10:8
SIRS no. (%) 63 (39.4%) 35 (33.2%) 22 (55.0%) 12
(66.7%)
Alcoholic hepatitis 56 (35.6%) 27 (33.3%) 25 (62.5%) 12
(66.7%)
no. (%)
Infection in prior 67(41.9%) 37(45.7%) 21(52.5%)
11(61.1%)
14 days: no. (%)
Child-Pugh score 9.6 1.8 10.0 1.9 11.6 1.3 11.6
1.5
MELD score 30.8 6.3 31.6 5.8 39.2 1.8 38.3 4.7
Table 7. Baseline Clinical & Laboratory Parameters
ACLF Grade 52 (n=242) ACLF Grade 3
(n=58)
159 83 40 18
Heart rate 77.8 15.8 82.0 15.1 84.9 14.3 90.9
12.1
(beats/min)
MAP (mmHg) 77.6 11.8 77.4 9.4 82.9 12.2 79.1 9.0
VVBC (x109/I) 8.9 6.1 8.7 5.2 11.3 5.0 11.4
6.2
INR 2.0 0.67 2.0 0.56 3.1 0.86 4.3 5.22
Creatinine (mg/di) 3.5 1.04 3.5 1.04 3.5 0.93 3.4 0.96
Bilirubin (mg/di) 9.4 11.3 11.7 12.5 27.1 12.2 29.2
19.8
Prior Albumin (g) 331 171 369 299 349 164 391 152
[00216] FIG. 5 is a graph showing 90-day survival of patients treated with and
without terlipressin according to ACLF grade. Patients with an ACLF grade of 3
and
treated with terlipressin had a lower likelihood of survival than patients
with an ACLF
grade of 0-2 and treated with terlipressin or patients treated with placebo
regardless of
ACLF grade. FIG. 6C shows the percent of patients with respiratory failure
among those
treated with terlipressin was similar to placebo for patients with an ACLF
grade of 0-2.
The percent of patients with respiratory failure in patients treated with
terlipressin with
an ACLF score of 3 was much higher than placebo. The rate of respiratory
failure in
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FIG. 6C was based on reporting of respiratory failure during the study by the
investigator.
[00217] Table 8 provides the odds ratio for additional baseline parameters as
predictors of respiratory failure with terlipressin use.
Table 8. Predictors of Respiratory Failure with Terlipressin Use
Parameter Odds Ratio P value
Baseline INR 1.81 0.011
Baseline MAP 1.037 0.037
Baseline Sp02 0.835 0.014
[00218] The results of Tables 4-6 indicate that terlipressin should be used
with
extreme caution in patients with HRS-1 and ACLF grade 3, especially in those
with
compromised oxygen saturation. Patients with low baseline Sp02 are at risk for
respiratory failure (RF) and increased mortality.
Example 4:
[00219] The following analyses were performed to evaluate the impact of the
proposed mitigation strategy on the incidence of liver transplantation and pre-
transplant
mortality of subjects listed at baseline in two prior terlipressin studies
(REVERSE
[Example 1] and CONFIRM [Example 2]). The mitigated population excludes data
from
subjects with baseline acute-on-chronic liver failure Grade 3 and baseline
serum
creatinine mg/dL, and subjects listed for transplant at baseline with
baseline MELD
?35.
[00220] The incidence of liver transplantation by Day 90 in the mitigated
population in CONFIRM was slightly higher in the terlipressin group compared
to the
placebo group (24.2% vs. 22.5%) in contrast to the intent-to-treat (ITT)
population
where the incidence of liver transplantation in the terlipressin group was
lower
compared to placebo (23.1% vs. 28.7%) (Table 9).
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Table 9. Incidence of Transplant by Day 90 in CONFIRM
Overall Population
Mitigated Population
Terlipressin n/N Placebo n/N (%) Terlipressin n/N
Placebo n/N (%)
(%) (%)
Received 46/199 (23.1) 29/101 (28.7) 32/132 (24.2)
16/71 (22.5)
Transplant by
Day 90
[00221] Similarly, the incidence of subjects listed at baseline who did not
receive a transplant and died by Day 90 was substantially reduced from 21.4%
(12
subjects) in the overall population to 11.4% (4 subjects) in the mitigated
population. Of
the 12 subjects listed at baseline in the overall population who did not
receive a
transplant and died by Day 90, 6 subjects were mitigated by excluding data in
subjects
with ACLF-3 and SCr mg/dL and an additional
2 subjects were mitigated with the
MELD 35 cut-off criteria (Table 10). Similar effects of the mitigation
strategy in the
terlipressin group were observed in the REVERSE study.
Table 10. Incidence of Patients Listed at Baseline Who did not Receive a
Transplant
and Died by Day 90 by Population in CONFIRM and REVERSE
REVERSE + CONFIRM REVERSE CONFIRM
Terlipressin Placebo Terlipressin
Placebo Terlipressin Placebo
n/N (%) n/N (%) n/N (%) n/N (%) n/N (%) n/N (%)
Overall 20/92 (21.7) 8/59 (13.6) 8/36 (22.2)
8/39 (20.5) 12/56 (21.4) 0/20 (0.0)
Population
Population 10/72(13.9) 7/44(15.9) 4/28(14.3)
7/30(23.3) 6/44(13.6) 0/14 (0.0)
ACLF &
SCr<5
Mitigated 6/53 (11.3) 6/35 (17.1) 2/18 (11.1)
6/25 (24.0) 4/35 (11.4) 0/10 (0.0)
Population
[00222] Due to the limited number of donor organs available in the US, only
about half of all wait-listed subjects in 2018 received a liver within one
year and many
patients die or are removed from the wait list without undergoing transplant
(Kwong
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2021). For example, 11.3% of all patients listed for liver transplant in 2016
died prior to
receiving a transplant (Kwong 2021), and the 90-day pre-transplant mortality
was 10.5%
overall and 25.7% in patients with a MELD score of 35 (Nagai 2018).
[00223] The pre-transplant mortality in the mitigated population in the
CONFIRM study and in the pooled dataset of the CONFIRM and REVERSE studies
was consistent with the published data for all US transplant-listed patients.
In
aggregate, these analyses provide that in patients receiving terlipressin, the
mitigation
strategy favorably impacts the incidence of liver transplantation and
minimizes the risk
that a patient listed for liver transplant will be precluded from receiving a
transplant due
to a potential adverse effect of terlipressin.
[00224] In the mitigated population in the CONFIRM study, there was a
clinically meaningful reduction in overall SAEs, respiratory failure SAEs,
overall fatal
AEs, fatal respiratory failure AEs, and overall mortality in the terlipressin
group
compared with the respective overall population (Table 11).
Table 11. Overview of Safety for the Overall and Mitigated Population in
CONFIRM
Overall Population (% of Subjects) Mitigated Population (% of Subjects)
Terlipressin Placebo (N=99)
Terlipressin Placebo (N=71)
(N=200) (N=132)
Serious Adverse 65.0 60.6 61.4
59.2
Events
Respiratory 13.5 5.1 9.8
7.0
failure
Any AE leading to 41.5 40.4 34.1
40.8
death up to 30
days post-
treatment
Respiratory 8.5 1.0 5.3
1.4
failure
Death by Day 30 39.0 36.4 31.8
36.6
Death by Day 60 47.0 41.4 40.2
Death by Day 90 51.0 44.4 44.7
45.1
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[00225] There was a clinically meaningful reduction in the incidence of
overall
SAEs and SAEs due to respiratory failure in the mitigated population in
CONFIRM
(Table 11). The between-group difference in the incidence of respiratory
failure SAEs in
the overall study population of 8.4% (13.5%-5.1%) was reduced to 2.8% (9.8%-
7.0%) in
the mitigated population. For the terlipressin group, the incidence of overall
SAEs in the
mitigated population is lower than in the overall study population without
mitigation
(61.4% vs. 65.0%, respectively). In the mitigated population, the incidence of
overall
SAEs in the terlipressin group was similar to the placebo group (61.4% vs.
59.2%,
respectively).
[00226] The incidence of overall AEs leading to death, fatal respiratory
failure
AEs, and overall mortality was substantially reduced in the mitigated
population in
CONFIRM. The between-group difference in the incidence of respiratory failure
fatal
AEs in the overall population of 7.5% (8.5%-1.0%) was reduced to 3.9% (5.3%-
1.4%) in
the mitigated population. The incidence of all AEs leading to death up to 30
days post-
treatment for the terlipressin group in the mitigated population is lower than
in the
overall population without mitigation (31.8% vs. 39.0%, respectively) and also
lower
than in the placebo group in the mitigated population (31.8% vs. 36.6%,
respectively).
[00227] The incidence of liver transplantation by Day 90 in the mitigated
population was slightly higher in the terlipressin group compared with the
placebo group
(24.2% vs. 22.5%, respectively) in contrast to the overall population, where
the
transplantation rate was lower (23.1% vs. 28.7%, respectively; Table 8).
Importantly, the
pre-transplant mortality by Day 90 of subjects listed for transplant at
baseline in the
terlipressin group was reduced from 21.4% in the overall population to 11.4%
in the
mitigated population (Table 10) and is within the range of what is reported in
all subjects
listed for liver transplantation in the US.
[00228] The benefit of terlipressin therapy on verified HRS reversal
demonstrated in the overall CONFIRM study population was also observed in the
mitigated population (Table 12). The benefit of terlipressin over placebo was
likewise
preserved for the secondary endpoints. The impact of the primary endpoint on
the key
clinical outcomes of renal replacement therapy (RRT) and RRT-free survival was
also
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maintained. Similar to overall population, in the mitigated population, the
incidence of
RRT was lower at all time points through Day 90 in the terlipressin group than
in the
placebo group.
Table 12. Overview of Efficacy for the Overall and Mitigated Population in
CONFIRM
Overall Population (% of Subjects)
Mitigated Population (% of Subjects)
Terlipressin Placebo p-value Terlipressin Placebo p-value
(N=199) (N=101) (N=132) (N=71)
Primary endpoint
Verified HRS 29.1 15.8 0.012 36.4 18.3
0.007
Reversal
Secondary
endpoint
HRS Reversal 36.2 16.8 <0.001 44.7 18.3
<0.001
Durability of HRS 31.7 15.8 0.003 38.6 18.3
0.003
reversal
HRS reversal in 33.3 6.3 <0.001 41.2 3.3
0.001
SIRS subgroup
Verified HRS 24.1 15.8 0.092 28.8 18.3
0.103
reversal without
HRS recurrence
by Day 30
Key Clinical
Outcome
Subjects with RRT 30.3 46.4 30.1 41.0
for alive subjects
by Day 90
[00229] The mitigated population is at a similar risk for undergoing RRT as
the
overall population as evidenced by the proportion of subjects who received RRT
up to
Day 90 (Table 13). In these subjects, RRT-free survival remained numerically
favorable
in the terlipressin group compared with the placebo group.
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Table 13. Subjects Alive Without RRT Though Day 90 in the Overall Population
and the
Mitigated Population in CONFIRM
Overall Population (% of Mitigated Population (% of
Subjects) Subjects)
Terlipressin Placebo
Terlipressin Placebo
(N=199) (N=101) (N=132) (N=71)
Subjects Alive without 114/146 (78.1) 47/77 (61.0)
87/107 (81.3) 36/55 (65.5)
RRT by Day 14
Subjects Alive without 89/121 (73.6) 37/65 (56.9)
70/90 (77.8) 29/45 (64.4)
RRT by Day 30
Subjects Alive without 75/105 (71.4) 32/60 (53.3)
57/79 (72.2) 25/41 (61.0)
RRT by Day 60
Subjects Alive without 69/99 (69.7) 30/56 (53.6)
51/73 (69.9) 23/39 (59.0)
RRT by Day 90
[00230] In the CONFIRM overall population, the overall survival estimate up to
Day 90 was numerically lower in the terlipressin group than in the placebo
group (48.2%
vs. 53.5%, respectively). In contrast, in the mitigated population, the
overall survival
estimate up to Day 90 was similar in the terlipressin group compared with the
placebo
group (55.3% vs 54.9%, respectively).
[00231] The risk mitigation strategy preserved the beneficial effects of
terlipressin as demonstrated in the overall CONFIRM study population (i.e.,
statistical
significance for primary endpoint, lower incidence of RRT, and favorable RRT-
free
survival with terlipressin compared with placebo). In the mitigated
population, there was
also a clinically meaningful reduction in risks compared with the overall
population,
including lower incidence of respiratory failure, overall mortality, and pre-
transplant
mortality. Therefore, the mitigated population represents a population where
the
benefits of terlipressin treatment outweigh the risks in this rare
complication of liver
disease associated with a high medical need and no current FDA-approved or
proven
pharmacological treatments.
[00232] Although the disclosure herein has been described with reference to
particular embodiments, it is to be understood that these embodiments are
merely
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illustrative of the principles and applications of the present disclosure. It
will be apparent
to those skilled in the art that various modifications and variations can be
made to the
devices, systems, and methods of the present disclosure without departing from
the
spirit and scope of the disclosure. Thus, it is intended that the present
disclosure include
modifications and variations that are within the scope of the appended claims
and their
equivalents.
[00233] Reference throughout this specification to "one embodiment," "certain
embodiments," "one or more embodiments" or "an embodiment" means that a
particular
feature, structure, material, or characteristic described in connection with
the
embodiment is included in at least one embodiment of the disclosure. Thus, the
appearances of the phrases such as "in one or more embodiments," "in certain
embodiments," in one embodiment" or in an embodiment" in various places
throughout
this specification are not necessarily referring to the same embodiment of the
disclosure. Furthermore, the particular features, structures, materials, or
characteristics
may be combined in any suitable manner in one or more embodiments.
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