WO2015063602A1

WO2015063602A1 - Desmopressin and blood glucose

Info

Publication number: WO2015063602A1
Application number: PCT/IB2014/002967
Authority: WO
Inventors: Jens Peter NØRGAARD
Original assignee: Ferring B.V.
Priority date: 2013-10-29
Filing date: 2014-10-28
Publication date: 2015-05-07

Abstract

The present disclosure is related to methods for reducing the random blood glucose levels of a subject by administering desmopressin.

Description

DESMOPRESSIN AND BLOOD GLUCOSE

Cross-Reference To Related Applications

[0001] This application claims the benefit under 35 U.S.C. § 1 19(e) to U.S. provisional application 61/897,034, filed October 29, 2013, the contents of which are incorporated herein by reference in their entirety.

Field

[0002] Described herein are compositions and methods for reducing random blood glucose levels, such as may be desired in patients with a recognized need for random blood glucose level lowering. For example, this random blood glucose lowering can be useful for preventing and treating diabetes, diabetic complications, insulin resistance and insulin resistance syndrome, for reducing the risks of such conditions and/or for delaying the onset or progression of such conditions.

Background

[0003] If glucose is ingested, alone or in the form of carbohydrates such as maltose, sucrose, or starch, in food or drink, the blood glucose level rises above normal levels. For healthy individuals, this hyperglycemic state is only temporary, as the glucose is quickly metabolized or otherwise utilized by the individual. The American Diabetes Association recognizes that before people develop type 2 diabetes, they almost always have

"prediabetes," in which blood glucose levels are higher than normal, but not yet high enough to be diagnosed as diabetes. As such prediabetic conditions continue into diabetes mellitus, glucose tolerance of the patient is reduced, and abnormally high random glucose levels are maintained for longer periods of time, a circumstance that is dangerous for a diabetic patient.

[0004] Carbohydrates which are ingested appear in the blood as glucose, and are metabolized into lipids (cholesterol, phospholipids, triglycerides, etc.). Excessive carbohydrate intake can lead to increased biosynthesis of such lipids, resulting in

hyperlipidemia and an accumulation of lipids, both in adipose tissue and in other systems in the organism. Atherosclerosis, obesity, myocardial infarction and other heart diseases may be some of the consequences of such glucose intolerance.

[0005] There remains a need, therefore, for compositions and methods for reducing random blood glucose levels.

Summary

[0006] The present disclosure relates to compositions and methods for reducing random blood glucose levels, wherein the compositions and methods comprise the administration of desmopressin. As discussed in more detail below, the present inventors have found that desmopressin can achieve clinically significant lowering of random blood glucose levels, including in human patients who have a recognized need for random glucose level reduction.

[0007] In specific embodiments, the present disclosure provides desmopressin or a pharmaceutically acceptable salt thereof for reducing the random blood glucose of a mammalian subject, by methods comprising administering to the subject a hypoglycemically effective amount of desmopressin. In some embodiments, the subject is selected as being in need of reduction of its random blood glucose levels. In some embodiments, the

administration of desmopressin decreases random blood glucose levels of the selected mammalian subject.

[0008] Thus, described herein are methods for reducing the blood glucose level of a mammalian subject in need thereof, comprising administering to the subject a

hypoglycemically effective amount of desmopressin or a pharmaceutically acceptable salt thereof. Also described are methods for reducing the blood glucose of a mammalian subject comprising: selecting a mammalian subject in need of reduction of its blood glucose, and administering to the selected mammalian subject, a hypoglycemically effective amount of desmopressin or a pharmaceutically acceptable salt thereof, whereby the administration of desmopressin of pharmaceutically acceptable salt thereof decreases the blood glucose of the selected mammalian subject.

[0009] In accordance with any methods described herein, the desmopressin may be in the form of desmopressin acetate. In accordance with any methods described herein, the hypoglycemically effective amount of desmopressin or a pharmaceutically acceptable salt thereof may be from about 0.5 to about 800 μg, or from about 1.0 to about 600 μg, In accordance with any methods described herein, the desmopressin or pharmaceutically acceptable salt thereof may be present in a pharmaceutical dosage form, such as an orodispersible dosage form, such as an orodispersible dosage form comprising an open matrix network comprising desmopressin, wherein the open matrix network comprises levan.

[0010] In accordance with any methods described herein, the methods may comprise at least once daily administration of desmopressin or a pharmaceutically acceptable salt thereof, such that a course of therapy may comprise at least once daily administration of desmopressin or a pharmaceutically acceptable salt thereof.

[0011] In accordance with any methods described herein, the method results in reduced random blood glucose levels in the subject of from about 70 mg/dL to about 200 mg/dL, from about 70 mg/dL to about 180 mg/dL, or from about 70 mg/dL to about 150 mg/dL. In accordance with any methods described herein, the reduced random blood glucose levels are achieved after a course of therapy of at least one day, at least one week, at least 2 weeks, at least one month, at least three months, at least six months, or at least twelve months.

[0012] Also provided is desmopressin or a pharmaceutically acceptable salt thereof, for reducing the blood glucose level of a mammalian subject in need thereof, such as in accordance with any method described herein.

[0013] Also provided are uses of desmopressin or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for reducing the blood glucose level of a mammalian subject in need thereof, such as in accordance with any method described herein.

Detailed Description

[0014] Particular aspects of the disclosure are described in greater detail below. The terms and definitions as used in the present application and as clarified herein are intended to represent the meaning within the present disclosure. The patent and scientific literature referred to herein and referenced above are hereby incorporated by reference. The terms and definitions provided herein control, if in conflict with terms and/or definitions incorporated by reference.

Terms and Definitions

[0015] The singular forms "a," "an," and "the" include the plural reference unless the context dictates otherwise.

[0016] The terms "approximately" and "about" mean to be nearly the same as a referenced number or value. As used herein, the terms "approximately" and "about" should be generally understood to encompass ± 10% of a specified amount, frequency or value. With regard to specific values, it should be understood that specific values described herein for subject populations (e.g., the subject of the described clinical trial) represent median values, unless otherwise indicated as, e.g., mean values. Accordingly, aspects of the present disclosure requiring a particular value in a subject are substantially supported herein by population data in which the relevant value is assessed to be a meaningful delimitation of the subject population.

[0017] As used herein the term "first sleep period" refers to the time elapsed from bedtime to either first void or morning rising.

[0018] The term "hyponatraemia" as used herein refers to a serum sodium value below the lower limit of the normal reference range, for example, a serum sodium level of less than 130 mmol/L. The term "nocturnal enuresis" as used herein refers to a condition in which a person who has bladder control while awake urinates while asleep. As used herein, the term "nocturnal polyuria" refers to an increased nocturnal output of urine. For example, a ratio of nighttime urine volume over the 24-hour urine volume to be equal to or greater than 33%.

[0019] The terms "administer," "administration," or "administering" as used herein refer to (1) providing, giving, dosing and/or prescribing, such as by either a health professional or his authorized agent or under his direction, and (2) putting into, taking or consuming, such as by the patient or person herself or himself. [0020] As used herein, the phrase "effective amount" means that dosage that provides the specific pharmacological effect for which the drug is administered (e.g., random blood glucose level lowering) in a subject in need to such treatment. It is emphasized that a therapeutically effective amount will not always be effective in treating the conditions described herein, even though such dosage is deemed to be a therapeutically effective amount by those of skill in the art. For convenience only, exemplary dosages and therapeutically effective amounts are provided below with reference to adult human subjects. Those skilled in the art can adjust such amounts in accordance with standard practices as needed to treat a specific subject and/or condition/disease.

[0021] As used herein, "desmopressin" refers to desmopressin and any pharmaceutically acceptable salt thereof, or any other pharmaceutically acceptable form (such as a hydrate or solvate), including desmopressin acetate.

Desmopressin Dosage Forms

[0022] Pharmaceutical dosage forms for use in the methods described herein may be adapted to supply the active ingredient to the oral cavity. Desmopressin may be absorbed across the sublingual mucosa, and/or otherwise from the oral cavity (e.g., across the buccal and/or gingival mucosa) and/or from the gastrointestinal tract for systemic distribution.

[0023] A variety of formulations are known which are suitable for delivering other active ingredients for absorption from the oral cavity. Such formulations may be useful in the methods described herein. Desmopressin typically is provided in a solid dosage form, optionally with a pharmaceutically acceptable carrier.

[0024] In some embodiments, desmopressin is provided in an orodispersible dosage form. As used herein, the term "orodispersible" indicates that the dosage form disintegrates rapidly in the mouth, for example, within 15 seconds, or within 10 seconds, or within 5 seconds, or within 2 seconds or even within 1 second.

[0025] Examples of these include intrabuccally disintegrating solid formulations and preparations which comprise the active ingredient, a sugar comprising lactose and/or mannitol and 0.12 w/w%, based on the solid components, of agar and which has a density of 400 mg/ml to 1000 mg/ml and have a sufficient strength for handling, which in practice may mean sufficient strength to withstand removal from a blister packaging without

disintegrating. Such formulations, and how to make them, are disclosed in U.S. Patent No. 5,466,464, which in incorporated herein by reference.

[0026] In one embodiment, the sugar may be used in the formulation in an amount of at least 50 w/w%, such as 80 w/w% or more, including 90 w/w% or more, based on the total solid components, although it may vary depending on the quality and quantity of the active ingredient to be used.

[0027] Orodispersible dosage forms can also be in the form of an open matrix network carrying pharmaceutically active ingredients, for example, desmopressin or pharmaceutically acceptable salts thereof, as generally described for example, in WO 2011/120904 and WO 2013/037708, each of which is incorporated herein in their entireties. Such open matrix networks can comprise materials such as levan (a polymeric form of fructose), or inulin (a polymeric form of fructose), or combinations thereof, and other pharmaceutically acceptable excipients, for example, mannitol, trehalose or raffinose. Such open matrix networks also rapidly disintegrate or dissolve in aqueous media or saliva.

[0028] Other formulations known for delivering active ingredients for absorption from the oral cavity are the dosage forms disclosed in U.S. Patent Nos. 6,024,981, 6,200,604 and 6,221,392.

[0029] Commercially available desmopressin melt tablets contain desmopressin acetate in a freeze-dried (lyophilized) presentation formulated with fish gelatin, mannitol and citric acid. The desmopressin melt tablet formulation disintegrates essentially instantaneously (for example, in less than about 10 seconds) in the mouth (for example, super- or sublingually) without the need for water.

[0030] This and other orodispersible pharmaceutical dosage forms of desmopressin with good bioavailability are described in, for example, U.S. Patent Nos. 7,560,429 and 7,947,654, the contents of which are hereby incorporated in their entireties. Other dosage forms may be prepared using desmopressin acetate, desmopressin free base, or another pharmaceutically acceptable salt of desmopressin.

[0031] Regardless of the specific form of desmopressin used, the desmopressin dosage is expressed herein in terms of the free base amount (e.g., the desmopressin moiety), even if the desmopressin is actually supplied as a salt, such as the acetate salt. Thus, except where otherwise indicated, the doses described herein reflect equivalent amounts of desmopressin free base, even though desmopressin acetate may have been used. For example, as used herein, a 100 μg dose of desmopressin refers to 100 μg of desmopressin free base equivalent, which corresponds to a proportionally higher amount of desmopressin acetate. In specific embodiments, for example, 100 μg of desmopressin may be provided by approximately 1 12.4 μg of desmopressin acetate which comprises 89% w/w desmopressin free base and 1 1% w/w (the balance) acetate, water and impurities. Similarly, 50 μg, 25 μg and 10 μg dosages of desmopressin refer to those amounts of desmopressin free base equivalent, such that the corresponding amounts of desmopressin acetate would be proportionately higher. As a general guideline, 0.1 mg of desmopressin acetate is deemed to be equivalent to about 89 μg of desmopressin free base.

[0032] Desmopressin may be formulated in strengths, measured as the free base, from about 0.5 or 1.0 μg to about 1 mg per dosage form. In specific embodiments, the strength will typically range from about 2 μg to about 800 μg desmopressin per dosage form or, for example, from about 10 μg to about 600 μg. Relatively low doses are also specifically contemplated, for example, from about 0.5 μg to about 75 μg, including from about 0.5 μg or 1.0 μg to about 50 μg.

[0033] In some embodiments, the desmopressin is administered once per day. When one dosage form per day is administered, the above listed doses will typically be the dose per dosage form. In some embodiments, the desmopressin is administered in divided doses, at the same time or at different times. When the daily dose is administered in two or more dosages, the amount of desmopressin per dosage form will be reduced accordingly.

[0034] Other active ingredients, whether or not peptides, may also be present. Methods

[0035] As noted above, described herein is desmopressin or a pharmaceutically acceptable salt thereof for reducing the random blood glucose of a mammalian subject, by methods that comprise administering desmopressin to a patient in need thereof, such as a patient selected as having a need for random blood glucose level reduction.

[0036] The patient may be a human or other mammal, and may be determined to be in need of random blood glucose level reduction, such as exhibiting glucose intolerance, being prediabetic, or being diabetic. For example, the patient may suffer from diabetes mellitus and/or from one or more conditions such as atherosclerosis, obesity, myocardial infarction, or other heart disease.

[0037] The desmopressin may be administered in any dosage form, such as those described above, at dosages described above. In some embodiments, the dose administered is effective to reduce the random blood glucose levels of the patient, e.g., is a hypoglycemically effective dose. In other embodiments, the dose administered is effective to achieve more specific random blood glucose target levels, as discussed below.

[0038] In some embodiments, the dose of desmopressin administered is from about 0.5 to about 800 μg, or from about 1.0 to about 600 μg. In some embodiments, the methods comprise administering a dose of desmopressin of from about 0.5 to about 800 μg a day, or from about 1.0 to about 600 μg a day, including from about 0.5 or 1.0 μg to about 1 mg, from about 2 μg to about 800 μg, from about 10 μg to about 600 μg, or from 0.5 μg to about 75 μg, including from about 0.5 μg or 1.0 μg to about 50 μg, per day, including 25 μg, 50 μg, or 75 μg per day, in a single dose or in two or more divided doses.

[0039] A course of therapy may comprise at least once daily administration of

desmopressin or a pharmaceutically acceptable salt thereof, such as at the dosages described above, or more frequent administration thereof, such as using divided doses of the dosages described above. A course of therapy may comprise at least a few days, e.g., 1-3 days, or a week, or up to one month, or two months, or several months, e.g., 3 months or 6 months or 12 months or more. [0040] Blood sugar levels can be measured with a glucose meter, which gives results in either mg/dL (milligrams per deciliter, favored in, for example, the United States), or in mmol/L (millimoles per liter, favored in, for example, Canada and Europe).

[0041] Glycemic control is a term which reflects typical levels of blood sugar (glucose) in a person with diabetes mellitus. Evidence suggests that many of the long-term complications of diabetes, especially the microvascular complications, result from many years of hyperglycemia (elevated levels of glucose in the blood). Good glycemic control, in the context of a treatment target, is considered an important goal of diabetes care.

[0042] "Perfect glycemic control" would mean that random blood glucose levels were always normal (about 70 to about 130 mg/dL or about 3.9 - 7.2 mmol/L). Practically, since treatment measures are imperfect, even "good glycemic control" describes random blood glucose levels that average somewhat higher than normal much of the time. Accepted target levels of random blood sugar that constitute good glycemic control have been reduced over the last 25 years, because of improvements in the diagnostic tools available for diabetic care, because of increasing evidence that glycemic control has value in controlling complications, and by the expectations of both doctors and patients. The concept of "good glycemic control" also depends on the age of a patient, and the degree of her susceptibility to hypoglycemia.

[0043] One particular measurement of blood glucose levels is a random blood glucose test. Blood glucose levels measured in this fashion typically exhibit values in the low- to mid- 100's (mg/dL). A random blood glucose level of about 180 mg/dL or higher is indicative of a condition of hyperglycemia, and a level of about 200 mg/dL or higher is indicative of the presence of or a risk for developing a disorder associated with impaired glucose regulation, e.g., diabetes.

[0044] In some embodiments, the methods described herein result in lower random blood glucose levels in the patient. In some embodiments, the methods described herein result in good glycemic control in the patient. [0045] Therefore, in one aspect, the present methods and compounds/compositions are useful for maintaining or achieving blood glucose levels, determined by random blood glucose test, at normal levels, i.e., low- to mid-100's (mg/dL). In a further aspect, the present methods and compounds/compositions can be used to lower/reduce random blood glucose levels which are elevated above normal levels, i.e., above low- to mid-100's (mg/dL). In various aspects, the present methods and compounds/compositions are effective to reduce elevated random blood glucose levels to levels below about 200 mg/dL and above about 70 mg/dL, for example, to levels below about 180 mg/dL and above about 70 mg/dL, including to levels below about 150 mg/dL and above about 70 mg/dL.

[0046] Reductions in random blood glucose such as those described herein may be achieved after a course of therapy that is at least a few days, e.g., 1-3 days, or a week, or up to one month, or two months, or several months, e.g., 3 months or 6 months or 12 months or more.

[0047] While not wanting to be bound by any theory, it is believed that the efficacy of desmopressin in this regard may be associated with sleep improvement associated with desmopressin therapy.

[0048] Previous studies have shown a correlation between sleep disruption and glucose metabolism.

[0049] In a study evaluating the effects of sleep disruption on glucose metabolism , eleven healthy normal volunteers were subjected to 2 nights of sleep fragmentation by auditory and mechanical stimuli after which they underwent an intravenous glucose tolerance test. See Stamatakis and Punjabi, Chest, 2010, 137(1): 95-101. Following two nights of sleep fragmentation, insulin sensitivity was decreased by 25% (p<0.0001). Sleep continuity is therefore an important regulator of systemic insulin sensitivity. It should be noted, however, that that sleep fragmentation altered sleep stage distribution in this study and was most notably associated with an increase in stage 1 sleep and a decrease in SWS (slow wave sleep) and REM (rapid eye movement) sleep. It may be this reduction in SWS, rather than fragmentation per se, which is responsible for the effects seen on glucose metabolism which are reminiscent of those found by Tasali et al. in relation to SWS suppression. See, Tasali, et al., Proc Natl Acad Sci USA, 2008, 105(3): 1044-9.

[0050] In an observational, cross-sectional study of 210 participants, (age range 30-54 years) in the University of Pittsburgh's Adult and Human Behavior Project (Jennings, et al, Sleep, 2007, 30(2): 219-23), poor global sleep quality scores of the PSQI were significantly associated with the presence of the metabolic syndrome. An increase of global sleep score of 2.6 points (approximately 1 SD) was associated with an odds of having the metabolic syndrome of 1.44 (p= 0.04, confidence interval = 1.01-2.06). Linear regression results showed that the PSQI global score was significantly related to waist circumference, body mass index, percentage of body fat, serum levels of insulin and glucose, and estimated insulin resistance.

[0051] In another cross-sectional study, this time of 3435 Taiwanese subjects, subjects with metabolic syndrome had significantly higher global PSQI (6.76 + 3.2 vs. 6.16 + 2.4, p<0.001) scores and a higher risk of being poor sleepers (PSQI score >5; 63.4% vs. 53.5%, pO.001) than those without metabolic syndrome, and this association persisted after adjustment for snoring (Hung, et al, PLoS One, 2013, 8(1): e54304). Of the five components of metabolic syndrome, hyperglycemia and low HDL-C were independently associated with the global PSQI scores, while low HDL-C was an independent predictor of being poor sleepers.

[0052] In a cross-sectional study of 161 African-American participants with type 2 diabetes, Knutson, et al. found that glycemic control was associated with perceived sleep debt but not PSQI score in those without diabetic complications (Knutson, et al, Arch. Intern. Med., 2006, 166: 1768-74). However, in patients with at least one complication, HbAlc level was associated with PSQI score but not perceived sleep debt. The predicted increase in HbAlc level for a 5-point increase in PSQI was 1.9% above the median.

[0053] An incremental improvement in additional minutes of sleep duration with desmopressin administration, when compared to traditional sedatives/hypnotics relative to placebo has been observed. Traditionally prescribed sleep medicaments such as Zolpidem, temazepam and zaleplon can provide approximately 22-30 minutes additional total sleep time relative to placebo (Ancoli-Israel et al, J. Clin. Psychiatry, (Primary Care Companion), 1999; 1 : 114-120, and Mitler et al, J. Clin. Pharmacology, 1979, 8: 635-685).

[0054] In contrast administration of 50 or 75μg desmopressin to male patients resulted in an increase in the First Undisturbed Sleep Period of approximately 39 minutes (Weiss et al, J. Urol, 2013, 190: 965-972), and administration of 25μg desmopressin to female patients resulted in an increase in the First Undisturbed Sleep Period of approximately 49 minutes (Sand et al, J. Urol, 2013, 190: 958-964).

[0055] Further aspects of the methods described herein are illustrated in the following examples, which are not limiting in any respect.

Example 1 - Efficacy and Safety of Low Dose Orally Disintegrating Tablet in Women with Nocturia - Results of a Multi-Center, Randomized, Double-Blind, Placebo- Controlled Parallel Group Study

[0056] This was a randomized, double-blind, placebo controlled, parallel group, multicenter study. This study was conducted at 39 primary and secondary care centers across the United States and Canada from November 2010 to November 2011. Eligible patients were females older than 18 years with nocturia (2 or more voids per night determined via a 3 -day bladder diary completed immediately before randomization). Of 649 screened subjects 268 were randomized to treatment. Key exclusion criteria included evidence of urinary disorders, polydipsia and hyponatremia (serum sodium less than 135 mmol/L). Patients on stable doses of overactive bladded (OAB) medication for 3 months were allowed to participate. The trial was performed in accordance with the Declaration of Helsinki and approved by the institutional review board/ethics committee for each site. All patients provided written informed consent.

[0057] Patients were randomized 1 : 1 to placebo or 25 μg desmopressin orally dissolving tablets (ODT) once daily using a computer generated list prepared before enrollment.

Randomization was stratified by age (younger than 65 vs. 65 years old or older).

Desmopressin and placebo orally dissolving tablets (ODT) were supplied by Ferring Pharmaceuticals, and were indistinguishable with respect to appearance, smell, taste and packaging.

[0058] Participants were instructed to empty their bladder before bed, drink only to satisfy thirst, and limit evening intake of fluids with a diuretic effect such as coffee, tea, caffeinated soft drinks and alcoholic beverages. Tablets were to be taken 1 hour before bedtime.

[0059] Patients completed 3 -day bladder and sleep diaries immediately before

randomization and after randomization at week 1 , month 1 , month 2 and month 3 to record the time and volume of nocturnal voids. Patients reported on sleep quality using the sleep rating scale (1— poor to 10— excellent). The Nocturia Quality of Life (N-QoL) and Work Productivity and Activity Impairment (WPAI) questionnaires were also completed. Patients rated each of the 13 N-QoL statements from 0 (lowest) to 4 (highest), where 1 statement concerns global QoL and 12 statements cover the specific disease. The raw scores were transformed into a standardized score out of 100. The WPAI outcomes were expressed as impairment percentages of 4 scores of absenteeism (work time missed), presenteeism

(impairment at work/reduced on-the-job effectiveness), work productivity loss (overall work impairment/absenteeism plus presenteeism) and activity impairment.

[0060] The Food and Drug Administration-requested co-primary efficacy end points were change from baseline in mean number of nocturnal voids and 33% responder status during 3 months of treatment using a longitudinal analysis. A 33% responder was defined as a patient with a decrease of at least 33% in the mean number of nocturnal voids at each visit compared to baseline. This end point captures information on the distribution of reductions.

[0061] Secondary end points included change from baseline at 3 months in mean number of nocturnal voids, proportion of 33% responders, mean time to first nocturnal void (the time from going to bed with the intention of sleeping to first void) and mean nocturnal urine volume. Exploratory end points included mean self-rated sleep quality, N-QoL scores and WPAI percentages.

[0062] Safety and tolerability were monitored at each visit via observation and assessment of adverse events (AEs). AEs were coded by the system organ class and preferred terms using MedDRA (the Medical dictionary for Regulatory Activities), and categorized by severity, seriousness and likelihood of causal relationship to study medication as determined by the investigator.

[0063] Serum sodium was measured during screening and on all study visits after treatment. If serum sodium was 130 mmol/L or less the patient was asked to visit the trial site as soon as possible for further evaluation. Patients with a serum sodium of 125 mmol/L or less were withdrawn from the study immediately.

[0064] Additional safety measurements included a standard battery of blood and urine analyses, vital signs and physical examinations. All patients who received 1 or more doses of the study drug or placebo and had 1 or more safety assessments were included in the safety analyses.

[0065] The trial was powered to demonstrate superiority to placebo simultaneously on the 2 co-primary end points. Using assumptions on means, variances and correlations of the number of voids at various points based on data from females in a previous trial (Weiss, et ah, Neurourol. Urodyn., 2012, 31 : 441), simulations demonstrated that a sample size of 130 patients per group yielded at least 95% power to detect 0.5 or more voids constant treatment effect as well as a statistically significant subsequent time averaged odds ratio of 33% responder status. All end points were analyzed based on the full analysis set that included all randomized and exposed patients with at least 1 efficacy assessment after dosing initiation. Two-sided tests were used for all efficacy end points.

[0066] Change from baseline in mean number of nocturnal voids was analyzed

longitudinally using a repeated measures ANCOVA (ANCOVA) with change in mean number of nocturnal voids as the dependent variable. The second co-primary end point, proportion of 33% responders, was analyzed using a generalized estimating equation method with the 33% responder status as the dependent variable. For both analyses observed values were used, baseline mean nocturnal voids was a covariate, and treatment, visit (including a treatment by visit interaction term) and age stratification (younger than 65, 65 years old or older) were factors. If the treatment by visit interaction was not significant at the 5% level, it was removed from the model. [0067] All secondary end points were tested using cross-sectional analyses at month 3 using the respective baseline as covariate, and age stratification and treatment as factors. Missing values were imputed using last observation carried forward. Exploratory end points were analyzed in a manner similar to the secondary end points. SAS® version 9.2 was used.

[0068] The most common reason for screening failure was nonfulfillment of the inclusion/exclusion criteria (49%), such as evidence of severe daytime voiding dysfunction, renal impairment and averaging less than 2 nocturnal voids during screening. Overall, 96% of randomized patients took greater than 80% of the planned doses (based on returned medication) and 89% completed the study. An equal percentage of patients prematurely discontinued in the desmopressin and placebo treatment groups. Two patients were randomized to placebo but received desmopressin, and they are included in the placebo group in the full analysis set. Overall, treatment groups were well balanced. All patients had a previous diagnosis of nocturia. Daytime frequency of 6 or more voids was reported by 40% to 50% of patients in the treatment groups and 5 patients were included despite having 8 or more voids at baseline. The most common concomitant medications were vitamins, lipid modifying agents, analgesics, anti-inflammatory agents and antirheumatic agents.

Example 2 - Efficacy and Safety of Low Dose Orally Disintegrating Tablet in Men with Nocturia - Results of a Multi-Center, Randomized, Double-Blind, Placebo-Controlled Parallel Group Study

[0069] This was a multicenter, randomized, double-blind, placebo controlled, parallel group study. This study was conducted at 50 primary and secondary care centers across the United States and Canada from February 2011 to January 2012. Eligible patients were males 18 years old or older with nocturia (2 or more voids nightly determined via a 3 -day frequency- volume chart completed immediately before randomization to treatment). Of 1,013 screened subjects 395 were randomized to treatment. The primary objective was to test the safety and efficacy of 50 and 75 μg desmopressin ODT vs placebo in men with nocturia during 3 months of treatment. Key exclusion criteria were evidence of severe daytime voiding dysfunction (more than 1 urge incontinence or urgency episode daily or more than 8 daytime voids per day in the 3-day diary), suspicion of BOO or a urine flow less than 5 ml per second, surgery for BOO or BPH within 6 months of screening, urinary retention and/or post-void residual volume greater than 250 ml (confirmed by ultrasound if investigator suspected retention), history of urological malignancies, neurogenic detrusor activity or current genitourinary tract pathology that could interfere with voiding, polydipsia and hyponatremia (serum sodium less than 135 mmol/L). Patients on stable doses of a-antagonists and/or antimuscarinic agents for 3 months were allowed to participate. The trial was performed in accordance with the Declaration of Helsinki and approved by the institutional review board/ethics committee for each site. All patients provided written informed consent.

[0070] Patients were randomized 1 : 1 : 1 to placebo, 50 μg desmopressin or 75 μg desmopressin once daily using a computer generated list prepared before study enrollment. Randomization was stratified by age (younger than 65 vs 65 years old or older).

Desmopressin and placebo ODT were supplied by Ferring Pharmaceuticals, and were indistinguishable with respect to appearance, smell, taste and packaging.

[0071] Patients were instructed to take the study drug every night 1 hour before bedtime, to drink only to satisfy thirst and to empty their bladder before bed. Evening intake of fluids with a diuretic effect such as coffee, tea, caffeinated soft drinks and alcoholic beverages was especially discouraged.

[0072] Patients completed 3 -day voiding and sleep diaries immediately before

randomization, after randomization, at week 1 , month 1 , month 2, month 3 and at the end of study part II to record the time and volume of voids and the time to the first nocturnal void. In the morning (before breakfast) patients also reported sleep quality using the sleep rating scale (1— poor/very tired to 10— excellent/wide awake). The Nocturia Quality of Life and Work Productivity and Activity Impairment questionnaires were also completed. Patients rated each of the 13 N-QoL statements from 0 (lowest) to 4 (highest), where 1 statement concerns global QoL and 12 cover the specific disease. Raw data were then transformed into a standardized score out of 100. The WPAI outcomes were expressed as impairment percentages of the 4 scores of absenteeism (work time missed), presenteeism (impairment at work/reduced on the job effectiveness), work productivity loss (overall work impairment/absenteeism plus presenteeism) and activity impairment. [0073] The co-primary efficacy end points were the change from baseline in mean number of nocturnal voids and proportion of 33% responders during 3 months of treatment analyzed using a longitudinal analysis. A 33% responder was defined as a patient with a decrease of at least 33% in the mean number of nocturnal voids at each visit compared to baseline.

[0074] Secondary end points included change from baseline at 3 months in mean number of nocturnal voids, proportion of 33% responders, mean time to first void and mean nocturnal urine volume. The exploratory end points included mean self-rated sleep quality, N-QoL scores and WPAI percentages.

[0075] Safety and tolerability were monitored via observation and assessment of AEs. These were coded by the system organ class and preferred terms using MedDRA, and categorized by severity, seriousness and likelihood of causal relationship to study medication as rated by the investigator.

[0076] AEs and serum sodium were measured during screening and on all study visits (day 4, week 1, month 1, month 2 and month 3) after treatment. If serum sodium was 130 mmol/L or less, the patient was asked to visit the trial site as soon as possible for further evaluation. Patients with a serum sodium of 125 mmol/L or less were withdrawn from the study immediately.

[0077] Additional safety measurements included a standard battery of blood and urine analyses, vital signs and physical examinations. All patients who received 1 or more doses of desmopressin or placebo were included in the safety analyses.

[0078] The trial was powered to demonstrate superiority to placebo simultaneously on the 2 co-primary end points. Using assumptions on means, variances and correlations of the number of voids at the various points based on data from men in a previous trial (Weiss, et ah, Neurourol. Urodyn., 2012, 31 : 441), simulations estimated that a sample size of 130 patients per group yielded at least 95% power to detect a treatment effect of 0.3 voids, as well as finding a subsequent statistically significant time averaged odds ratio of 33% responder status. [0079] Testing was performed using a hierarchical step-down approach. The 75 μg dose had to be significant at the 2-sided 5% nominal significance level on both co-primary end points vs placebo before testing the 50 μg, thereby protecting the overall Type 1 error to be 5% or less.

[0080] All primary, secondary and exploratory end points were analyzed based on the full analysis set which included all randomized and exposed patients with at least 1 efficacy assessment after dosing initiation. Two-sided tests were used for all efficacy end points.

[0081] Change from baseline in mean number of nocturnal voids was analyzed longitudinally using a repeated measures ANCOVA with change in mean number of nocturnal voids as the dependent variable. The second co-primary end point, proportion of 33% responders, was analyzed using a generalized estimating equation method with the 33% responder status as the dependent variable. For both analyses observed values were used, baseline mean nocturnal voids was a covariate, and treatment, visit (including a treatment by visit interaction term) and age stratification (younger than 65, 65 years old or older) were factors. If the treatment by visit interaction was not significant at the 5% level, it was removed from the model.

[0082] All secondary end points were tested using cross-sectional analyses at month 3, using respective baseline as covariate, and age stratification and treatment as factors.

Missing values were imputed using last observation carried forward. The exploratory end points were analyzed in a manner similar to the secondary end points. SAS® version 9.2 was used.

[0083] The most common reason for screening failure was nonfulfillment of the inclusion/exclusion criteria (53%) such as evidence of severe daytime voiding dysfunction (16%), renal impairment (16%) and averaging less than 2 nocturnal voids during screening (1 1%). Example 3 - Glucose Reduction

[0084] Exploratory, mediational analyses examining the role of changes in First

Undisturbed Sleep Period (FUSP) were undertaken on the data generated from Examples 1 and 2, detailed above. Specifically, analyses of pooled data from these trials showed that lengthening of the First Undisturbed Sleep Period by one hour, as resulted from desmopressin administration, is associated with a significant reduction in random blood glucose levels, as shown below (Table 1).

Table 1. Association of FUSP hourly increase with random blood glucose decrease in desmopressin-treated subjects*

[0085] *The data in Table 1 arise from a linear regression of the data. Repeated measures on long-term (>3 month data only) change in non-fasting glucose levels, adjusting for baseline non-fasting glucose level, age, baseline FUSP time (logarithmic) and change in FUSP as time-dependent covariate. Parameter estimates shown only for time-dependent change to FUSP.

[0086] Furthermore, an increase (94% of cases; 6% stable) in FUSP to > 4 hours (i.e., longer than the first two sleep cycles) over 3 months was associated with a reduction of 0.24 mmol/L in random blood glucose (4.4 mg/dL) as shown in Table 2. Table 2. Association of reduction in glucose with increase in FUSP to > 4 hours (data pooled across clinical trials in desmopressin-treated subjects) with ITT, minimum 3 months [n=601]; with >/= 3 months [n=394]

[0087] The results shown here indicate the impact of desmopressin on FUSP, the clinical significance of FUSP as a marker for sleep which is associated with sleep quality and quantity, and the association between FUSP and random blood glucose levels.

[0088] Taken together, these data are important because they validate improvements in FUSP by reference to a conventional measure of sleep quality (PSQI), and that desmopressin- induced increases in FUSP are associated with increases in total sleep duration. These data also demonstrate that FUSP > 4 hours (longer than 2 sleep cycles) is associated with achieving healthy (low-risk) total duration of sleep.

[0089] Importantly, these data indicate that desmopressin-induced increases in FUSP are associated with clinically significant decreases in random blood glucose levels, and that FUSP > 4 hours (longer than 2 sleep cycles) is associated with significantly reduced random blood glucose levels.

Claims

What is claimed is:

1. A method for reducing the blood glucose level of a mammalian subject in need thereof, comprising administering to the subject a hypoglycemically effective amount of desmopressin or a pharmaceutically acceptable salt thereof.

2. A method for reducing the blood glucose of a mammalian subject comprising:

selecting a mammalian subject in need of reduction of its blood glucose, and administering to the selected mammalian subject, a hypoglycemically effective amount of desmopressin or a pharmaceutically acceptable salt thereof, whereby the administration of desmopressin of pharmaceutically acceptable salt thereof decreases the blood glucose of the selected mammalian subject.

3. The method of claim 1 or claim 2, wherein the desmopressin is present in the form of desmopressin acetate.

4. The method of claim 1 or claim 2, wherein the hypoglycemically effective amount of desmopressin or a pharmaceutically acceptable salt thereof is from about 0.5 to about 800 μg.

5. The method of claim 4, wherein the hypoglycemically effective amount of desmopressin or a pharmaceutically acceptable salt thereof is from about 1.0 to about 600 μg.

6. The method of claim 1 or claim 2, wherein the desmopressin or pharmaceutically acceptable salt thereof is present in a pharmaceutical dosage form.

7. The method of claim 6, wherein the pharmaceutical dosage form is an orodispersible dosage form.

8. The method of claim 7, wherein the orodispersible dosage form comprises an open matrix network comprising desmopressin, wherein the open matrix network comprises levan.

9. The method of claim 1 or claim 2, wherein the method results in reduced random blood glucose levels in the subject of from about 70 mg/dL to about 200 mg/dL.

10. The method of claim 9, wherein the method results in reduced random blood glucose levels in the subject of from about 70 mg/dL to about 180 mg/dL.

11. The method of claim 10, wherein the method results in reduced random blood glucose levels in the subject of from about 70 mg/dL to about 150 mg/dL.

12. The method of claim 9, wherein the reduced random blood glucose levels are achieved after a course of therapy of at least one day.

13. The method of claim 12, wherein the reduced random blood glucose levels are achieved after a course of therapy of at least one week.

14. The method of claim 13, wherein the reduced random blood glucose levels are achieved after a course of therapy of at least 2 weeks.

15. The method of claim 14, wherein the reduced random blood glucose levels are achieved after a course of therapy of at least one month.

16. The method of claim 15, wherein the reduced random blood glucose levels are achieved after a course of therapy of at least three months.

17. The method of claim 16, wherein the reduced random blood glucose levels are achieved after a course of therapy of at least six months.

18. The method of claim 17, wherein the reduced random blood glucose reduction levels are achieved after a course of therapy of at least twelve months.

19. The method of claim 12, wherein the course of therapy comprises at least once daily administration of desmopressin or a pharmaceutically acceptable salt thereof.

20. Desmopressin or a pharmaceutically acceptable salt thereof, for reducing the blood glucose level of a mammalian subject in need thereof.

21. Desmopressin or a pharmaceutically acceptable salt thereof, for reducing the blood glucose level of a mammalian subject in need thereof by a method comprising selecting a mammalian subject in need of reduction of its blood glucose, and administering to the selected mammalian subject, a hypoglycemically effective amount of desmopressin or a pharmaceutically acceptable salt thereof, whereby the administration of desmopressin of pharmaceutically acceptable salt thereof decreases the blood glucose of the selected mammalian subject.

22. The desmopressin or pharmaceutically acceptable salt thereof of claim 20 or 21 , wherein the desmopressin is present in the form of desmopressin acetate.

23. The desmopressin or pharmaceutically acceptable salt thereof of claim 20 or 21 , wherein the hypoglycemically effective amount of desmopressin or a pharmaceutically acceptable salt thereof is from about 0.5 to about 800 μg.

24. The desmopressin or pharmaceutically acceptable salt thereof of claim 20 or 21 , wherein the hypoglycemically effective amount of desmopressin or a pharmaceutically acceptable salt thereof is from about 1.0 to about 600 μg.

25. The desmopressin or pharmaceutically acceptable salt thereof of claim 20 or 21 , wherein the desmopressin or pharmaceutically acceptable salt thereof is present in a pharmaceutical dosage form.

26. The desmopressin or pharmaceutically acceptable salt thereof of claim 25, wherein the pharmaceutical dosage form is an orodispersible dosage form.

27. The desmopressin or pharmaceutically acceptable salt thereof of claim 26, wherein the orodispersible dosage form comprises an open matrix network comprising desmopressin, wherein the open matrix network comprises levan.

28. The desmopressin or pharmaceutically acceptable salt thereof of claim 20 or claim 21 , for reducing random blood glucose levels in the subject to from about 70 mg/dL to about 200 mg/dL.

29. The desmopressin or pharmaceutically acceptable salt thereof of claim 20 or claim 21 , for reducing random blood glucose levels in the subject to from about 70 mg/dL to about 180 mg/dL.

30. The desmopressin or pharmaceutically acceptable salt thereof of claim 20 or claim 21 , for reducing random blood glucose levels in the subject to from about 70 mg/dL to about 150 mg/dL.

31. The desmopressin or pharmaceutically acceptable salt thereof of claim 20 or claim 21 , for reducing random blood glucose levels after a course of therapy of at least one day.

32. The desmopressin or pharmaceutically acceptable salt thereof of claim 20 or claim 21 , for reducing random blood glucose levels after a course of therapy of at least one week.

33. The desmopressin or pharmaceutically acceptable salt thereof of claim 20 or claim 21 , for reducing random blood glucose levels after a course of therapy of at least 2 weeks.

34. The desmopressin or pharmaceutically acceptable salt thereof of claim 20 or claim 21 , for reducing random blood glucose levels after a course of therapy of at least one month.

35. The desmopressin or pharmaceutically acceptable salt thereof of claim 20 or claim 21, for reducing random blood glucose levels after a course of therapy of at least three months.

36. The desmopressin or pharmaceutically acceptable salt thereof of claim 20 or claim 21 , for reducing random blood glucose levels after a course of therapy of at least six months.

37. The desmopressin or pharmaceutically acceptable salt thereof claim 20 or claim 21 , for reducing random blood glucose levels after a course of therapy of at least twelve months.

38. The desmopressin or pharmaceutically acceptable salt thereof of claim 20 or claim 21, wherein the course of therapy comprises at least once daily administration of desmopressin or a pharmaceutically acceptable salt thereof.

39. Use of desmopressin or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for reducing the blood glucose level of a mammalian subject in need thereof.