Combined Use of an Alpha-Adrenergic Receptor Antagonist and an Anti-Muscarinic Agent

Abstract

The combined use of (R)-5-(2-{[2-(2-ethoxyphenoxy)ethyl]amino}propyl)-2-methoxybenzene-1-sulfonamide (tamsulosin), or its pharmaceutically acceptable salt, and (1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid (3R)-quinuclidin-3-yl ester (solifenacin), or its pharmaceutically acceptable salt, for the preparation of a medicament for the improvement of lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH) with a substantial storage component is provided.

Claims

1. A method of improving storage symptoms in a male human patient having lower urinary tract symptoms associated with prostatic hyperplasia (LUTS/BPH) with a substantial storage component, the method comprising administering to the male human patient (R)-5-(2-{[2-(2-ethoxyphenoxy)ethyl]amino}propyl)-2-methoxybenzene-1-sulfonamide (tamsulosin) or a pharmaceutically acceptable salt thereof in an amount of 0.4 mg per day, and simultaneously or sequentially administering (1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid (3R)-quinuclidin-3-yl ester (solifenacin) or a pharmaceutically acceptable salt thereof in an amount of 6 mg to 9 mg per day.

2. The method according to claim 1, wherein the pharmaceutically acceptable salt of (R)-5-(2-{[2-(2-ethoxyphenoxy)ethyl]amino}propyl)-2-methoxybenzene-1-sulfonamide is (R)-5-(2-{[2-(2-ethoxyphenoxy)ethyl]amino}propyl)-2-methoxybenzene-1-sulfonamide hydrochloride.

3. The method according to claim 2, wherein the (R)-5-(2-{[2-(2-ethoxyphenoxy)ethyl]amino}propyl)-2-methoxybenzene-1-sulfonamide hydrochloride is used in an amount of 0.4 mg.

4. The method according to claim 2, wherein the (R)-5-(2-{[2-(2-ethoxyphenoxy)ethyl]amino}propyl)-2-methoxybenzene-1-sulfonamide hydrochloride is used in a modified-release formulation or in a modified-release part of a combination composition.

5. (canceled)

6. The method according to claim 1, wherein the pharmaceutically acceptable salt of (1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid (3R)-quinuclidin-3-yl ester is (1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid (3R)-quinuclidin-3-yl ester succinate.

7. (canceled)

8. The method according to claim 6, wherein the (1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid (3R)-quinuclidin-3-yl ester succinate is used in an amount of 6 mg, or 9 mg.

9. The method according to claim 6, wherein the (1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid (3R)-quinuclidin-3-yl ester succinate is used in an immediate release formulation or in an immediate release part of a combination composition.

10. A method of improving storage symptoms in a male human patients having lower urinary tract symptoms associated with prostatic hyperplasia (LUTS/BPH) with a substantial storage component, the method comprising administering to the male human patient (R)-5-(2-{[2-(2-ethoxyphenoxy)ethyl]amino}propyl)-2-methoxybenzene-1-sulfonamide or a pharmaceutically acceptable salt thereof in an amount of 0.4 mg per day and (1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid (3R)-quinuclidin-3-yl ester or a pharmaceutically acceptable salt thereof in an amount of 6 mg to 9 mg per day in a fixed-dose combination composition, wherein the lower urinary tract symptoms is characterized by a total International Prostatic Symptom Scoring (I-PSS) of 13 or higher, and the substantial storage component is characterized as ≧8 micturitions/day and ≧1 urgency episode grade 3 or 4/day according to Patient Perception of Intensity and Urgency Scale (PPIUS).

11. (canceled)

12. The method according to any of claims 1-4, 6 and 8-9 wherein the lower urinary tract symptoms are 13 or higher on a total I-PSS and the substantial storage component is ≧8 micturitions/day and ≧1 urgency episode grade 3 or 4/day on a PPIUS.

13. The method according to claim 12 wherein the substantial storage component is ≧8 micturitions/day and ≧2 urgency episodes of grade 3 and 4/day on a PPIUS.

14. The method according to claim 12 wherein the substantial storage component is ≧8 micturitions/day and ≧3 urgency episodes of grade 3 and 4/day on a PPIUS.

15. The method according to claim 12 wherein the substantial storage component is ≧8 micturitions/day, ≧2 urgency episodes of grade 3 and 4/day on a PPIUS and a Qmax of 4-15 mL/s.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0013] After extensive studies the present inventors found that the combined use of (R)-5-(2-{[2-(2-ethoxyphenoxy)ethyl]amino}propyl)-2-methoxybenzene-1-sulfonamide or a pharmaceutically acceptable salt thereof and (1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid (3R)-quinuclidin-3-yl ester or a pharmaceutically acceptable salt thereof demonstrated to be of benefit for the preparation of a medicament for improving storage symptoms in male patients suffering from lower urinary tract symptoms associated with prostatic hyperplasia (LUTS/BPH) with substantial storage symptoms, as diagnosed by means of a total I-PPS-score (LUTS/BPH) and number of micturitions/day and urgency episodes/day (storage symptoms) respectively.

[0014] The present inventors further surprisingly found that the combined use of in particular tamsulosin hydrochloride and solifenacin succinate showed that the same combination had no or even an deteriorating effect on male patients having lower urinary tract symptoms associated with benign prostatic hyperplasia, without a substantial storage component.

[0015] Tamsulosin or its salt is known as an adrenaline a receptor antagonist (U.S. Pat. No. 4,703,063; patent document 1) and its chemical structure is shown below. Tamsulosin is also known as YM617.

##STR00001##

[0016] Tamsulosin or its pharmaceutically acceptable salt, an effective ingredient of the pharmaceutical composition of the present invention, is easily available by the methods described, for example, in the aforementioned patent document 1, or by methods obvious to the person skilled in the art, or by any modifications thereof. Preferably as the first active ingredient (R)-5-(2-{[2-(2-ethoxyphenoxy)ethyl]amino}propyl)-2-methoxybenzene-1-sulfonamide hydrochloride or tamsulosin hydrochloride is used.

[0017] This active ingredient can be used in an amount of 0.2 mg or 0.4 mg, dependent on the population to be treated. Normally this active ingredient is included in a modified-release formulation, e.g. in the form of coated granules in a capsule (commercially available as OMNIC® or HARNAL® capsules) or in the form of coated matrix tablets (commercially available as OMNIC OCAS® tablets). Alternatively, the active ingredient can be incorporated in a modified-release part of a combination composition.

[0018] Solifenacin or its salt is known as a muscarinic receptor antagonist (International patent Publication WO No. 96/20194; patent document 2) and its chemical structure is shown below. Solifenacin is also known as YM905.

##STR00002##

[0019] Solifenacin or its pharmaceutically acceptable salt, an effective ingredient of the pharmaceutical composition of the present invention, is easily available by the methods described, for example, in the aforementioned patent document 2, or by methods obvious to the person skilled in the art, or by any modifications thereof.

[0020] Preferably, as the second active ingredient, (1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid (3R)-quinuclidin-3-yl ester succinate or solifenacin succinate is used.

[0021] Dependent on the population to be treated this active ingredient can be used in an amount of 2.5 mg, 5.0 or 10.0 mg or in an amount of 3 mg, 6 mg or 9 mg. The active ingredient is incorporated in an immediate release dosage form, e.g. in the form of a coated tablet (commercially available as VESICARE® tablet), or in an immediate release part of a combination dosage-form.

[0022] The “pharmaceutically acceptable salts” in “tamsulosin or its pharmaceutically acceptable salt” and “solifenacin or its pharmaceutically acceptable salt” are the same as the salts described in the aforementioned Patent Document 1 or the aforementioned Patent Document 2, respectively. Their specific examples are addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, or with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, and glutamic acid, and salts with inorganic bases such as sodium, potassium, magnesium, calcium, aluminium, or with organic bases such as methylamine, ethylamine, ethanolamine, lysine, and ornithine, and salts with various amino acids and amino acid derivatives such as acetylleucine, ammonium salts, and others.

[0023] Furthermore, the “pharmaceutically acceptable salts” in “tamsulosin or its pharmaceutically acceptable salt” and “solifenacin or its pharmaceutically acceptable salt” may be various hydrates, solvates and polymorphic crystalloids, which are all included as active ingredients for the preparation of the pharmaceutical compositions to be used in accordance with the present invention. The present invention also includes the use of various radioactive or non-radioactive isotope-labeled compounds for the preparation of a pharmaceutical composition to be used according to the invention.

[0024] The above-mentioned products, containing the first active ingredient, tamsulosin hydrochloride and the second active ingredient, solifenacin succinate, can also form part of a kit.

[0025] The present invention provides the use of (R)-5-(2-{[2-(2-ethoxyphenoxy)ethyl]amino}propyl)-2-methoxybenzene-1-sulfonamide or a pharmaceutically acceptable salt thereof for the preparation of a medicament which is simultaneously or sequentially administered with a medicament containing (1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid (3R)-quinuclidin-3-yl ester or a pharmaceutically acceptable salt thereof for improving storage symptoms in male patients having lower urinary tract symptoms associated with prostatic hyperplasia (LUTS/BPH) with a substantial storage component.

[0026] Further, it provides the use of (1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid (3R)-quinuclidin-3-yl ester or a pharmaceutically acceptable salt thereof for the preparation of a medicament which is simultaneously or sequentially administered with a medicament containing (R)-5-(2-{[2-(2-ethoxyphenoxy)ethyl]amino}propyl)-2-methoxybenzene-1-sulfonamide or a pharmaceutically acceptable salt thereof for improving storage symptoms in male patients having lower urinary tract symptoms associated with prostatic hyperplasia (LUTS/BPH) with a substantial storage component.

[0027] Also, the present invention provides the use of (R)-5-(2-{[2-(2-ethoxyphenoxy)ethyl]amino}propyl)-2-methoxybenzene-1-sulfonamide or a pharmaceutically acceptable salt thereof and (1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid (3R)-quinuclidin-3-yl ester or a pharmaceutically acceptable salt thereof for the preparation of a fixed-dose combination composition for improving storage symptoms in male patients having lower urinary tract symptoms associated with prostatic hyperplasia (LUTS/BPH) with a substantial storage component.

[0028] Advantageously the 2 active ingredients are used in fixed dose combination compositions, wherein (R)-5-(2-{[2-(2-ethoxyphenoxy)ethyl]amino}propyl)-2-methoxybenzene-1-sulfonamide hydrochloride or tamsulosin hydrochloride is used in an amount of 0.4 mg and (1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid (3R)-quinuclidin-3-yl ester succinate or solifenacin succinate is used in an amount of 3 mg, 6 mg or 9 mg, preferably 6 mg or 9 mg.

[0029] The pharmaceutical compositions for use in accordance with the present invention can be prepared by usually employed methods with tamsulosin or its pharmaceutically acceptable salt and solifenacin or its pharmaceutically acceptable salt along with carriers, excipients, or other additives for usual drug formulation. Administration can be performed orally in the forms of tablets, pills, capsules, granules, powders, liquids and the like, or parenterally in the forms of intra-articular, intravenous, or intramuscular injections, suppositories, ophthalmic solutions, ointments, percutaneous liquids, ointments, transdermal patches, transmucosal liquids, transmucosal patches, or inhalants. Oral administration can be cited as a preferred aspect.

[0030] As solid compositions for oral administration, tablets, powders, granules, and the like are used. In these solid compositions, the effective ingredient is mixed with at least one of inert excipients, and the like. The composition may follow conventional methods to contain inert additives such as lubricants, disintegrators, stabilizers, or solubilisers. If necessary, tablets and pills may be covered with sugar or gastric- or enteric-coating films.

[0031] Liquid compositions for oral administration contain pharmaceutically acceptable emulsifiers, solubilisers, suspensions, syrups, or elixirs, and the like. They also contain generally employed inert diluents such as purified water or ethanol. These liquid compositions may also, in addition to inert diluents, adjuvants such as solubilisers, humidifiers or suspensions, or sweetening agents, flavoring agents, aromatic agents, or antiseptic agents.

[0032] Injections for parenteral administration contain aseptic aqueous or non-aqueous solubilisers, suspensions, or emulsifiers. Aqueous solvents include, for example, distilled water for injection or physiological saline. Such compositions may further contain isotonising agents, antiseptic agents, humidifying agents, emulsifying agents, dispersing agents, stabilising agents or solubilising agents. These may be sterilized by filtration through, for example, a bacterium-retaining filter, addition of a sterilizer, or irradiation. These may also be prepared by preparing solid compositions aseptically and then solubilising or suspending them in sterilized water or a sterilized solvent for injection.

[0033] Topical preparations include ointments, plasters, creams, jellies, epithems, nebulas, lotions, ophthalmic solutions or ointments, and the like. They contain generally employed ointment bases, lotion bases, aqueous or non-aqueous liquids, suspending agents, emulsifying agents, and the like.

[0034] Transmucosal agents such as inhalants or transnasal agents utilize solids, liquids, or semi-liquids, and they can be prepared by conventional methods. For example, known excipients, or further, pH adjusters, antiseptics, surfactants, lubricants, stabilizers, or thickeners may properly be added. Drug administration may be aided by appropriate devices for inhalation or insufflation. For example, by using known devices such as pre-measured inhalation devices or nebulizers, a compound can be administered alone or as a formulated mixture in a powder, or in combination with pharmaceutically acceptable carriers in a solution or suspension. Dry-powder inhalers may be for single or multiple dosage of dry powder or powder-containing capsules, or may be assisted by a pressurized aerosol sprayer utilising appropriate gases such as chlorofluoroalkanes, hydrofluoroalkanes, or carbon dioxide as propellants.

[0035] Combination administration in the present invention may be performed by administering two drugs simultaneously, one immediately after the other, or with a desired time interval between them. When administered simultaneously, the two drugs may be administered in a combination composition, that is a single dosage-form in which both effective ingredients are contained, or in two separate formulations, each containing the effective ingredient, which are administered simultaneously.

[0036] The combined use of the 2 active ingredients, tamsulosin hydrochloride and solifenacin succinate is particularly useful for improving the symptoms of patients having Lower Urinary Tract Symptoms, associated with Benign Prostatic Hyperplasia (LUTS/BPH) wherein the severity of the lower urinary tract symptoms has been characterized by a total I-PSS score of 13 or higher and wherein the substantial storage symptoms have been characterized as ≧8 micturitions/day and ≧1, preferably ≧2 and more preferably ≧3 urgency episodes/day. More particularly the patients have urgency episodes, which are characterized as grade 3 or 4 according to PPIUS. (PPIUS stands for Patient Perception of Intensity and Urgency Scale, which ranges from zero to four with grades three and four representing severe urgency and urgency incontinence. PPIUS has been recommended by the Committee for Proprietary Medical Products when assessing the degree of urgency felt by patients at each micturition.) PPIUS scores for assessing urgency are:

TABLE-US-00001 Intensity of Score urgency Description 0 None I felt no need to empty my bladder but did so for other reasons 1 Mild I could postpone voiding as long as necessary without fear of wetting myself 2 Moderate I could postpone voiding for a short while without fear of wetting myself 3 Severe I could not postpone voiding but had to rush to the toilet in order not to wet myself 4 Urge I leaked before arriving at the toilet incontinence

[0037] More particularly the combined use of the first active ingredient and the second active ingredient in accordance with the above has been shown to be very useful for improving the lower urinary tract symptoms associated with BPH in male patients, the symptoms having been characterised by a total score of I-PSS of 13 or higher and wherein the substantial storage symptoms have been characterized as ≧8 micturitions/day, 2 urgency episodes of grade 3 and 4/day (PPIUS) and a Qmax of 4-15 mL/s.

[0038] The International Prostatic Symptom Scoring (I-PSS) is one of the criteria to evaluate the severity of lower urinary tract symptoms described above, and is used to judge the severity by scoring responses to the following questions: [0039] (1) During the last month, have you had a sensation of residual urine after urinating? [0040] (2) During the last month, have you had to urinate again in less than two hours after you have urinated? [0041] (3) During the last month, have you experienced interrupted urination? [0042] (4) During the last month, have you found it difficult to postpone urination? [0043] (5) During the last month, have you had a weak urinary stream? [0044] (6) During the last month, have you had to strain to urinate? [0045] (7) During the last month, how many times did you typically have to get up to urinate after you went to bed till you got up in the morning?

[0046] Out of these questions, the responses to (1) through (6) are scored as 0 if the response was not at all, 1 if less than 1 time in 5, 2 if less than 1 time in 2, 3 if about 1 time in 2, 4 if more than 1 time in 2, and 5 if almost always, and the responses to (7) are scored as 0, 1, 2, 3, 4, and 5 if the response was none, 1 time, 2 times, 3 times, 4 times, and 5 times or more, respectively.

The indices (1), (3), (5), and (6) are those to evaluate voiding symptoms, and (2), (4), and (7) are those to evaluate storage symptoms.

[0047] Patients whose total 1-PSS scores are 13 or higher are diagnosed as severe enough to be treated in accordance with the method of the present invention. However, a substantial storage component should be present, otherwise the patients will not benefit from the combined use of tamsulosin hydrochloride and solifenacin succinate.

[0048] The example further illustrates the invention.

Example

[0049] In a single-blind, 2-week placebo run-in period followed by a randomized, double-blind, parallel group, placebo-controlled, 12-week treatment period multi-center dose-ranging study, male patients having LUTS associated with BPH who had voiding symptoms (including incomplete emptying of the bladder, intermittency, weak stream or hesitancy) and storage symptoms (including frequency, urgency or nocturia) for months, the severity of their symptoms being characterised by a total International Prostate Symptom Score (I-PSS) of ≧13 and a maximum urinary flow rate of ≧4.0 mL/s and ≦15.0 mL/s with a voided volume ≧120 mL, were randomized to 1 of the following 8 treatments: [0050] placebo, [0051] monotherapy of 0.4 mg tamsulosin hydrochloride in a modified-release OCAS formulation (commercially available as OMNIC OCAS® tablets), [0052] monotherapy of 3, 6, or 9 mg respectively of solifenacin succinate in an immediate release tablet formulation or [0053] combination therapy of 0.4 mg of tamsulosin hydrochloride in a modified-release OCAS formulation (commercially available as OMNIC OCAS® tablets) in combination with 3, 6, or 9 mg respectively of solifenacin succinate in an immediate release tablet formulation.
Throughout the placebo run-in period, subjects took 2 placebo tablets once daily. Throughout the 12-week double-blind treatment period, subjects took 2 tablets once daily (tamsulosin hydrochloride OCAS 0.4 mg or placebo and solifenacin succinate 3, 6 or 9 mg or placebo). Study medication was taken orally in the morning with or without food. Medication was taken with a glass of water and was swallowed whole.

Efficacy Analyses Results:

[0054] Analyses were carried out on subpopulations based on the severity of baseline storage symptoms. The subpopulations investigated were Storage symptoms subgroups 1, 2 and 3, with a daily micturition frequency ≧8 and ≧1, 2 or 3 urgency episodes of grade 3 and 4 per day (PPIUS), respectively. The fourth subgroup was the Limited storage symptoms subgroup, whose baseline symptoms did not meet the criteria for Storage symptoms subgroup 1. Total urgency score, the mean sum of all urgency grades (PPIUS) per day was added as a new parameter.

Summary of I-PSS Data:

[0055] Opposite treatment effects were seen between the Limited storage symptoms subgroup and the Storage symptoms subgroups. [0056] When using higher doses of solifenacin in combination with tamsulosin OCAS alone, a deterioration was seen in the Limited storage symptoms subgroup for total I-PSS score, whereas the Storage symptoms subgroups 1, 2 and 3 showed a non-statistically significant trend to improvement. [0057] A deterioration in the I-PSS voiding scores was seen for all subgroups, when using combination treatment versus tamsulosin monotherapy. The only statistically significant slope with increasing dosages of solifenacin and in the presence of tamsulosin was in the Limited storage symptoms subgroup (p=0.0006). [0058] For I-PSS storage scores, all 3 subgroups with Storage symptoms showed a statistically significant improvement in the 3 different combination treatment arms versus monotherapy and in dose response (p=0.0016, p<0.0001, p=0.0006 respectively), while the Limited storage symptoms subgroup showed a not statistically significant deteriorating trend. [0059] All 3 subgroups with Storage symptoms showed a statistically significant trend to improvement in the I-PSS QoL score (p=0.0094, p=0.0008 and p=0.0106 respectively) with solifenacin-tamsulosin OCAS combination therapy compared to tamsulosin OCAS alone, while the Limited storage symptoms subgroup showed a statistically significant deteriorating trend (see Table 2).

TABLE-US-00002 TABLE 2 Parametric modeling results: change from baseline to endpoint in I-PSS scores showing estimated difference between solifenacin - tamsulosin OCAS combination versus tamsulosin OCAS in subpopulations based on severity of baseline storage symptoms (FAS) Sol Limited storage Storage Symptoms Parameter dose All subjects Symptoms Subgroup 1 Subgroup 2 Subgroup 3 I-PSS Total n 704 348 344 282 225 3 mg 0.14 0.85 −0.65 −0.81 −0.59 6 mg −0.01 0.80 −0.63 −1.13 −1.44 9 mg 1.00 2.59 *0.0013 −0.87 −1.72 −1.56 slope ↓0.0026 I-PSS n 704 348 344 282 225 Voiding 3 mg 0.49 0.78 0.06 0.1 0.47 6 mg 0.40 0.57 0.35 0.17 −0.01 9 mg 1.33 *0.0009 2.18 *0.0002 0.25 −0.12 0.05 slope ↓0.0022 ↓0.0006 I-PSS n 704 348 344 282 225 Storage 3 mg −0.32 0.15 −0.7 *0.0484 −0.88 *0.0286 −0.96 *0.0389 6 mg −0.41 0.24 −0.98 *0.0071 −1.28 *0.0022 −1.38 *0.0045 9 mg −0.33 0.44 −1.12 *0.0021 −1.6 *0.0001 −1.59 *0.0008 slope ↑0.0016 ↑<0.0001 ↑0.0006 I-PSS-QoL n 703 343 348 281 224 3 mg −0.13 0.17 −0.45 *0.0171 −0.5 *0.0153 −0.49 *0.0380 6 mg −0.01 0.31 −0.31 −0.5 *0.0189 −0.38 9 mg −0.06 0.40 *0.0277 −0.58 *0.0025 −0.77 *0.0004 −0.70 *0.0043 slope ↓0.0196 ↑0.0094 ↑0.0008 ↑0.0106 Sol dose = solifenacin dosage in mg in combination with tamsulosin OCAS 0.4 mg; Difference on left and significant p-value on right of column; n = total number of subjects in the subgroup with relevant data at any dose of solifenacin; *statistically significant (p < 0.05); ↑statistically significant slope showing improvement; ↓statistically significant slope showing deterioration (p < 0.05)

Summary of Micturition Diary Data:

[0060] Storage symptoms subgroups 2 and 3 showed a statistically significant dose-related improvement on all parameters, when adding solifenacin to tamsulosin OCAS versus tamsulosin OCAS alone. The solifenacin 6 mg-tamsulosin OCAS combination group showed a statistically significant improvement on all parameters, and the solifenacin 9 mg-tamsulosin OCAS combination group on total urgency score, frequency and voided volume (see Table 3.) [0061] A statistically significant dose-related improvement for urgency episodes of grade 3 and 4 (PPIUS) was seen in Storage symptoms subgroups 2 and 3 (p=0.0128 and p=0.0241, respectively), when using solifenacin-tamsulosin OCAS combination treatment versus tamsulosin alone. There was also a statistically significant improvement for the 6 mg solifenacin-tamsulosin OCAS combination arm versus tamsulosin monotherapy in the 3 subgroups with Storage symptoms. [0062] For total urgency score there was a statistically significant improvement for the 3 subgroups with Storage symptoms (p=0.0013, p=0.0004 and p=0.0038, respectively), and a statistically significant improvement for both the 6 and 9 mg solifenacin-tamsulosin OCAS combination arms versus tamsulosin OCAS monotherapy in the 3 subgroups with Storage symptoms. [0063] The 3 subgroups with Storage symptoms showed a statistically significant dose-related improvement for frequency (p=0.0004, p=0.0003 and p=0.0032, respectively), and all 3 dosages of the solifenacin-tamsulosin OCAS combination arms versus tamsulosin OCAS monotherapy showed a statistically significant improvement. [0064] When adding solifenacin to tamsulosin OCAS voided volume showed a statistically significant dose-related improvement for all 4 subgroups versus tamsulosin OCAS monotherapy (p<0.0001, p=0.0003, p=0.0042 and p=0.0067, respectively), and also a statistically significant improvement for the 9 mg solifenacin-tamsulosin OCAS combination arm versus tamsulosin OCAS monotherapy in all 4 subgroups.
The positive results in Storage symptoms subgroup 1 were mainly driven by the positive results in Storage symptoms subgroup 2.

TABLE-US-00003 TABLE 3 Parametric modeling results: change from baseline to endpoint in micturition diary data showing estimated difference between solifenacin - tamsulosin OCAS combination versus tamsulosin OCAS in subpopulations based on severity of baseline storage symptoms (FAS) Sol Limited storage Storage Symptoms Parameter dose All subjects Symptoms Subgroup 1 Subgroup 2 Subgroup 3 Urgency n 465 124 341 280 224 ¾ 3 mg −0.1 −0.14 −0.15 −0.06 0.07 6 mg −0.83 *0.0075 −0.24 −0.95 *0.0165 −1.14 *0.0138 −1.47 *0.0078 9 mg −0.24 0.24 −0.47 −0.81 −0.78 slope ↑0.0128 ↑0.0241 Total n 678 335 341 280 224 Urgency 3 mg −1.18 −1.15 −1.65 −1.79 −1.57 score 6 mg −1.96 *0.0055 −0.53 −3.36 *0.0028 −3.93 *0.0026 −4.57 *0.0029 9 mg −1.24 0.18 −3.2 *0.0042 −4.08 *0.0017 −3.57 *0.0166 slope ↑0.0437 ↑0.0013 ↑0.0004 ↑0.0038 Frequency n 699 347 342 280 224 3 mg −0.49 *0.0131 −0.1 −0.88 *0.0040 −0.9 *0.0112 −1.01 *0.0129 6 mg −0.66 *0.0009 −0.35 −0.94 *0.0028 −0.96 *0.0086 −1.03 *0.0163 9 mg −0.64 *0.0012 −0.2 −1.16 *0.0002 −1.4 *0.0001 −1.3 *0.0019 slope ↑0.0008 ↑0.0004 ↑0.0003 ↑0.0032 Voided n 699 347 342 280 224 volume 3 mg 6.3 2.23 10.06 6.46 5.90 6 mg 18.3 *<0.0001 21.49 *0.0010 14.26 *0.0341 10.18 11.93 9 mg 24.4 *<0.0001 26.11 *<0.0001 24.45 *0.0003 21.51 *0.0048 21.37 *0.0097 slope ↑<0.0001 ↑<0.0001 ↑0.0003 ↑0.0042 ↑0.0067 Sol dose = solifenacin dosage in mg in combination with tamsulosin OCAS 0.4 mg; Difference on left and significant p-value on right of column; n = total number of subjects in the subgroup with relevant data at any dose of solifenacin; *statistically significant (p < 0.05); ↑statistically significant slope showing improvement; ↓statistically significant slope showing deterioration (p < 0.05)