CA2624011A1 - Normalization or remission of microalbuminuria - Google Patents
Normalization or remission of microalbuminuria Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A—HUMAN NECESSITIES
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Abstract
A method of normalizing microalbuminuria in a patient, comprising administering to the patient in need thereof a therapeutically effective amount of an angiotensin II antagonist.
Description
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 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, 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 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 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;
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 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, 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 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 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 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;
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 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 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.
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 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 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.
Claims (19)
1. A method of normalizing microalbuminuria in a patient, comprising administering to the patient in need thereof a therapeutically effective amount of an angiotensin II
antagonist.
antagonist.
2. The method according to claim 1, wherein the administration of a therapeutically effective amount of an angiotensin II antagonist is repeated for a treatment period.
3. The method according to claim 1, wherein the patient is diabetic.
4. The method according to claim 3, wherein the diabetic patient's urine has more than 300 mg of albumin per gram of creatinine.
5. The method according to claim 4, wherein the diabetic patient's urine has between 30 and 300 mg of albumin per gram of creatinine.
6. The method according to claim 1, wherein the ratio of albumin to creatinine in the patient's urine is reduced to less than 30 mg of albumin per gram of creatinine.
7. The method according to claim 1, wherein the patient is a renal transplant patient.
8. The method according to claim 1, wherein the patient is a pediatric patient.
9. The method according to claim 1, wherein the treatment period is between 10 to 100 weeks.
10. The method according to claim 9, wherein the treatment period is between 10 to 50 weeks.
11. A method of persistently normalizing microalbuminuria in a patient having elevated levels of albumin in their urine comprising repeatedly administering a therapeutically effective amount of an angiotensin II antagonist to the patient for a treatment period.
12. The method according to claim 11, wherein the treatment period is between 10 to 100 weeks.
13. The method according to claim 12, wherein the treatment period is between 10 to 50 weeks.
14. The method according to claim 1, wherein the angiotensin II antagonist is candesartan, eprosartan, irbesartan, losartan, olmesartan, tasosartan, telmisartan, or valsartan.
15. The method according to claim 14, wherein the angiotensin II antagonist is telmisartan.
16. The method according to claim 1, further comprising administering a therapeutically effective amount of hydrochlorothiazide to the patient.
17. A method of normalizing microalbuminuria in responsive patients in a patient group consisting of patients having elevated levels of albumin in their urine, comprising administering a therapeutically effective amount of an angiotensin II
antagonist to each patient.
antagonist to each patient.
18. The method according to claim 17, wherein more than 30% of the total patients are responsive.
19. 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 medicament to normalize microalbuminuria in a diabetic patient.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US72227405P | 2005-09-30 | 2005-09-30 | |
| US60/722,274 | 2005-09-30 | ||
| PCT/US2006/036269 WO2007040966A1 (en) | 2005-09-30 | 2006-09-18 | Normalization or remission of microalbuminuria |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2624011A1 true CA2624011A1 (en) | 2007-04-12 |
Family
ID=37726683
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002624011A Abandoned CA2624011A1 (en) | 2005-09-30 | 2006-09-18 | Normalization or remission of microalbuminuria |
Country Status (4)
| Country | Link |
|---|---|
| AR (1) | AR058678A1 (en) |
| CA (1) | CA2624011A1 (en) |
| TW (1) | TW200727896A (en) |
| WO (1) | WO2007040966A1 (en) |
-
2006
- 2006-09-18 CA CA002624011A patent/CA2624011A1/en not_active Abandoned
- 2006-09-18 WO PCT/US2006/036269 patent/WO2007040966A1/en active Application Filing
- 2006-09-29 AR ARP060104299A patent/AR058678A1/en unknown
- 2006-09-29 TW TW095136270A patent/TW200727896A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| AR058678A1 (en) | 2008-02-20 |
| TW200727896A (en) | 2007-08-01 |
| WO2007040966A1 (en) | 2007-04-12 |
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