Note: Descriptions are shown in the official language in which they were submitted.
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NORMALIZATION OR REMISSION OF MICROALBUMINURIA
Field of the Invention
The present invention relates to a medicinal preparation of an angiotensin II
receptor
antagonist to achieve normalization of microalbuminuria in a diabetic patient.
Background of the Invention
In patients with impaired renal function, administration of an angiotensin II
antagonist or a
composition containing such antagonist is described to prevent end stage renal
failure, to
delay the progression of renal disease, or to slow the development of end
stage renal
disease (ESRD). In this context, losartan is observed to lead to an average
reduction of
proteinuria of 35%, i.e., a ratio of more than 300 mg of albumin per gram of
creatinine in
the patient's urine (WO 92/092081).
Microalbuminuria (MA), i.e., the presence of microgram quantities of albumin
in the urine,
of patients with diabetes mellitus (DM) is considered an early signal
heralding the onset of
systemic vasculopathy and associated target organ damage including cardiac and
renal
disease. Type 2 DM patients have a 28.2% prevalence of MA and 7.6% of clinical
proteinuria. Without intervention, 20-40% of these patients with MA progress
to
nephropathy and then ESRD. This percentage would be higher in the absence of
the high
frequency of cardiovascular death (CVD), which means MA correlates with
nephropathy,
ESRD, and CVD. The HOPE (Heart Outcomes Prevention Evaluation) trial noted a
continuous association of MA with cardiovascular (CV) events in patients with
DM even
below the albumin/creatinine threshold of 30 mg of albumin per gram of
creatinine. This
relationship also holds for non-diabetic patients with chronic kidney disease
(CKD).
There is yet no proof that MA could be used as an early marker of renal
disease
progression and nothing is known about a correlation of antiproteinuric
effects with
renoprotective effects. Improvements observed with medications that affect
blood pressure
(BP) such as renin-angiotensin-system (RAS) inhibitors might be effective due
to BP
lowering. Studies with angiotensin II receptor blockers (ARBs) in patients
having Type 2
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DM suggest that the level of proteinuria in patients treated with ARBs is more
predictive
of a renal outcome than the level of proteinuria at the start of a treatnient.
A recent trial
(Andersen et al., Diabetes Care 26(12), 2003) indicates that irbesartan migllt
have a long
tenn effect on MA which, in adults, persists after cessation of the
medication.
Thus, MA appears to be continuously associated with the development of renal
disease.
Presuming that normalization of MA is a more predictive marker for improving
the risk of
a renal disease as compared to reduction of proteinuria, the present invention
is based in
the surprising finding that treatment with an ARB such as telmisartan achieves
a
nonnalization of MA in at least 30% of type 2 DM patients which is
significantly above
the spontaneous remission rate of MA. This finding suggest normalization of MA
to be an
effective therapeutic and preventive treatment which achieves a reduction of
the risk of
renal disease development.
Summary of the Invention
One aspect of the present invention is a method of normalizing
microalbuminuria in a
diabetic patient coinprising administering a therapeutically effective amount
of an
angiotensin II antagonist or a composition containing an angiotensin II
antagonist.
Definition of Ternis and Conventions Used
Terms not specifically defined herein should be given the meanings that would
be given to
them by one of skill in the art in light of the disclosure and the context. As
used in the
specification and appended claims, however, unless specified to the contrary,
the following
terms have the meaning indicated and the following conventions are adhered to.
Methods of diagnosing microalbuminuria and measuring levels of albumin and
creatinine
are determined by any of several analytical or diagnostic methods known to one
of skill in
the art including classical chemical methods, the use of test strips or
indicator dyes,
spectrophotometric methods, HPLC and other chromatographic methods, capillary
electrophoresis, enzymatic methods, immunoprecipitation, radioimmunoassays,
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immunoassays with latex bodies, fluoroimmunoassays, enzyme immunoassays,
agglutination inhibition, immunoturbidimetry, immunonephelometry, and radial
immunodiffusion assays (see, e.g., D.E. Busby and G.L. Barkris, J. Clin.
Hypertension 6
(11 Suppl. 3):8-12 (2004); R.D. Toto, J. Clin. Hypertension 6 (11 Suppl. 3):2-
7 (2004);
G.L. Myers et al., Clin. Chem. 52(1):5-18 (2006); D. Sviridov et al., Clin.
Chem.
52(3):389-397 (2006); J.W. Brinkman et al., Clin. Chem. 51(11):2181-2183
(2005); T.M.
Osicka and W.D. Comper, Clin. Chem. 50(12):2286-2291 (2004); T. Niwa et al.,
Clin.
Chim. Acta 186:391-396 (1990); C.P. McCormik et al., Ann. Clin. Lab Sci.
19:944-951
(1989); C.L. Cambiaso et al., Clin. Chem. 34:416-418 (1988); C. Close et al.,
Diabet. Med.
4:491-492 (1987); A. Harmoinen et al., Clin. Chim. Acta 166:85-89 (1987); M.
Marre et
al., Clin. Chem. 33:209-213 (1987); A. Silver et al., Clin. Chem. 32:1303-1306
(1986);
Watts et al., Clin. Chem. 32:1544-1548 (1986); H. Keen et al., Lancet 2:913-
916 (1968);
and U.S. Patent Nos. 4,023,933; 5,077,222; 5,194,390; 5,385,847; and
6,756,230, and the
references cited therein, each of which is hereby incorporated by reference).
Microalbuminuria or MA exists wlien a patient has a ratio of albumin (mg) to
creatinine
(g) in their urine which is above 30 mg/g, preferably 30 mg/g to 300 mg/g, and
more
preferably 30 mg/g to 200 mg/g on a first morning void as tested or determined
by any one
of the various diagnostic methods known to one of skill in the art, e.g., that
are disclosed in
the references cited herein. Preferably the determination should be confirmed
on at least 2
consecutive measurements.
Albuminuria or proteinuria exists when a patient has a ratio of albumin (mg)
to creatinine
(g) in their urine which is above 300 mg/g on a first morning void as tested
or determined
by any one of the various diagnostic methods known to one of skill in the art,
e.g., that are
disclosed in the references cited herein. Preferably the determination should
be confirmed
on at least 2 consecutive measurements.
The term "remission" or "normalization" of MA in a patient means reducing the
ratio of
albumin (mg) to creatinine (g) their urine below 30 mg/g, preferably 20 mg/g
to 0 mg/g,
more preferably 3 mg/g to 0 mg/g, and most preferably 1 mg/g to 0 mg/g as
tested or
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determined by any one of the various diagnostic methods known to one of skill
in the art,
e.g., that are disclosed in the references cited llerein.
The term "persistent remission" or "persistent normalization" of MA in a
patient means
remission or normalization of MA after the administration of the angiotensin
II antagonist
to the patient has been discontinued.
Diabetic patients are diagnosed according to methods and protocols lcnown to
those of skill
in the art. Diabetic patients might be qualified as type 1 or type 2 diabetic
patients.
Particularly preferred are diabetic renal transplant patients. The most
preferred group of
diabetic patients are pediatric patients, that is, children 4 to 18 years of
age and particularly
children 6 to 16 years of age.
To achieve the goal of normalization of MA the treatment with an angiotensin
II antagonist
should last for at least 10 weeks. A preferred period of treatment is 10 to
100 weeks or 10
to 50 weeks, however, the goal might be achieved earlier while the treatment
with the
angiotensin II antagonist is continued with the intention to maintain the
blood pressure
control achieved by the antagonist. Following this treatment regime, an MA
remission rate
of 20-30% or 30-40% or even higher can be achieved. Frequently continued
nornlalization
of MA is observed after withdrawal of the angiotensin II antagonist
medication.
Preferred angiotensin II receptor blockers (ARBs) or angiotensin II
antagonists are the
ones already available for the treatment of hypertension such as candesartan,
eprosartan,
irbesartan, losartan, ohnesartan, tasosartan, telmisartan, or valsartan either
alone or in
combination with the diuretic hydrochlorothiazide. Particularly preferred is
telmisartan
sold under the trademark MICARDIS or, if combined with hydrochlorothiazide,
as
MICARDIS HCT.
In view of the above, another aspect of the present invention is the use of an
angiotensin II
antagonist selected from the group consisting of candesartan, eprosartan,
irbesartan,
losartan, olmesartan, tasosartan, telmisartan, or valsartan for the
preparation of a
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medicament to normalize and/or persistently normalize microalbuminuria in a
diabetic
patient.
Example
A randomized, double-blind, multi-center, forced-titration, parallel-group
study comparing
two doses of telmisartan with placebo in the treatment of MA in children with
DM 6 years
to 16 years of age is performed with the primary objective to show that
telmisartan is
superior to placebo in the percentage of diabetic (Type 1 and Type 2)
pediatric patients that
achieve a normalization of MA.
The primary endpoint is the percentage of patients that achieve a
normalization of MA
(defined as less than 30 mg albumin/g creatinine on a first morning void)
between Visit 2
(baseline) and Visit 6 (week 12). MA is defined as 30 to 300 mg albumin/g
creatinine on a
first morning void while proteinuria is defined as >300 mg albumin/g
creatinine on a first
morning void. This determination should be confirmed on at least 2 consecutive
measurements.
Secondary endpoints are:
1. change from baseline of microalbuminuria/albuminuria to end of initial
three month
treatment period for low or high dose telmisartan compared to placebo group;
2. change from baseline and end of 3 month treatment period to end of study
period at 9
months in microalbuminuria/albuminuria;
3. change in microalbuminuria/albuminuria from end of 9 months where
telmisartan is
withdrawn to 12 months;
4. MA responder rates with responders defmed as subjects who achieve remission
of MA
at the end of 3 month treatment period/end of placebo period and at the end of
the study
and observe how many patients remain in remission after withdrawal of the
telmisartan;
5. multiple regression model for correlates of reduction in
microalbuminuria/albuminuria
including telmisartan dose, casual BP and ambulatory BP reduction (including
night
time BP), glucose control as measured by QUICKI and glycosylated hemoglobin,
left
ventricular hypertrophy determined by echocardiography, lipid levels, C-
reactive
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protein, duration of diabetes, or GFR. All are to be measured at baseline, 3
months, 6
months, 9 months, and 12 months;
6. change froin baseline in seated systolic blood pressure (SBP) and diastolic
blood
pressure (DBP) to end of 3 month treaianent period as measured by (a) casual
BP or (b)
ambulatory BP measurement;
7. BP responder rates with responders defined as subjects who reach BP control
defined as
a seated SBP and/or DBP of <90th and 95th percentile for age, gender and
height at the
end of the treatment period. As long as the SBP is not Stage 2 hypertension
based on
the 4th Working Group Report on High Blood Pressure in Children, i.e., >99th
percentile plus 5 mmHg for SBP or DBP, no additional medications will be added
in the
3 month treatment period (Falkner 2004). In the next 6-9 month period,
additional
medications (excluding ACE-I or other ARBs) will be added to achieve BP
control
(<90th percentile).
A majority of the patients are normotensive and do not require any additional
antihypertensives. The study adheres to the following scheme:
Screening P hase (7-14 days): identification of patients and obtaining consent
Washout Phase (weeks -2 to 0): washout of previous antihypertensive or other
medication
not allowed by protocol if safe to do so and with home BP monitoring
MA Double Blind Phase (weeks 0-12): the dose titration scheme covers
= An initial dose phase (0-2 weeks) randomizing the medication to placebo, the
low or
high dose group with the actual dose determined by the weight group as shown
in the
table below, and
= a forced escalation (2-12 weeks) increasing the medication to full dose of
placebo, low
or high dose tehnisartan
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Table 1: Telmisartan Treatment Groups
Patient Weight Dose Titration Low Dose High Dose
20 - < 401cg Initial 5 mg (0.17 mg/kg) 20 mg (0.67 iug/lcg)
Final 10 mg (0.34 mg/kg) 40 mg (1.33 mg/kg)
40 -< 601cg Initial 10 mg (0.2 mg/kg) 40 mg (0.8 mg/lcg)
Final 20 mg (0.33 mg/kg) 80 mg (1.3 mg/kg)
60 kg Initial 20 mg (0.2 mg/kg) 60 mg (0.67 mg/kg)
Final 40 mg (0.4 mg/kg) 120 mg (1.33 mg/lcg)
No additional antihypertensives can be added to any group. Patients will be
exited from
the study if the blood pressure reaches stage 2 hypertension (99th percentile
plus 5 mmHg)
on two consecutive readings one day apart or if the patient becomes
symptomatic. The
primary endpoint for this trial, will be the percentage of patients that
achieve a
normalization of microalbumiiiuria and will be measured at week 12.
BP control phase: (weeks 12-40): Patients will be maintained in their blinded
dose group or
placebo but additional antihypertensives, other than ACE inhibitors or other
ARBs, will be
added as needed to achieve a BP level below the 90th percentile for age,
gender or height
or <130/80 which ever is lower. Diuretics will be suggested as first line
additional agent.
Calcium channel blockers will be discouraged.
Telmisartan Washout Phase (weeks 40-52): Telmisartan or placebo will be
withdrawn over
the first 2 weeks. Other antihypertensives will be continued and BP maintained
in the
normal range.
Statistics:
The primary endpoint, rate of normalization of MA at the end of twelve weeks
of treatment
are analyzed using the Cochran-Mantel-Haenszel test stratified by center.
Pairwise
comparisons are perfomled in a hierarchical fashion so as to not require an
adjustment in
the alpha level. The first comparison is made between the High dose
telrnisartan group and
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placebo. If this proves to be statistically significant at an alpha=0.05 level
then the second
comparison between the Low dose telmisartan group and placebo is performed.
Sample Size
It is assumed that patients who are not treated (an estimate for a placebo
response) have a
rate of normalization of 10%. The study is designed to detect a 20 percentage
point
improvement in the telmisartan treatment arm (30% normalization rate) over the
placebo
arm. This requires about 92 patients per treatment a.rm. To ensure sufficient
numbers of
patients complete the twelve weeks of treatment assuming that approximately
30% of the
patients do not complete the study the sample size is inflated to 130 patients
per treatnlent
arm for a total of 390 patients.
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