[001] This application is a continuation-in-part of U.S. Application No.

12/469,801 , filed May 21, 2009, which claims the benefit of U.S. Provisional Application No. 61/055,120, filed May 21 , 2008, the disclosures of which are incorporated herein by reference in their entireties.

[002] Only recently has nocturia been recognized as a clinical entity in its own right as opposed to one of many symptoms comprising various lower urinary tract conditions. It is currently defined by the International Continence Society (ICS) as the complaint that the individual has to wake up at night one or more times to void. This applies to any number of voids at any time during the night provided the person is awake before voiding. (1) In general, the term nocturia refers to urination at night, especially when excessive. It is also referred to as "nycturia."

[003] There are three broad categories of pathophysiology which account for nocturia: global polyuria; bladder storage problems; and nocturnal polyuria. (2)

[004] Global polyuria is defined as urine output > 40ml/kg body weight during a 24 hour period. Causes of polyuria include diabetes mellitus, diabetes insipidus, and primary thirst disorders.

[005] Bladder storage problems are characterized by frequent voids with small urine volumes. Causes of bladder storage problems include detrusor over activity (neurogenic and non-neurogenic); bladder hypersensitivity; bladder outlet obstruction; primary bladder pathology such as cystitis, calculi and neoplasia; and urogenital aging. A pattern of frequent waking and voiding is also characteristic of a primary sleep disturbance which should be part of the differential diagnosis in the evaluation of a patient with nocturia.

[006] Nocturnal polyuria is defined as the production of an abnormally large volume of urine during sleep. Healthy young adults from 21-35 years of age excrete approximately 14 ± 4% of their total urine between the hours of 11 p.m. and 7 a.m. whereas older people excrete an average of 34 ± 15%. (3-4) The ICS currently defines nocturnal polyuria as a nocturnal urine volume greater than 20 - 30% of total 24 hour urine volume, depending on age and in the absence of polyuria. (5)

[007] Nocturnal polyuria may be secondary to systemic conditions such as congestive heart failure, peripheral edema due to venous stasis or lymphostasis, renal or hepatic failure, lifestyle patterns such as excessive nighttime drinking, and

obstructive sleep apnea. Several studies suggest that some individuals with nocturia may have a loss of the normal circadian rhythmicity of arginine vasopressin (AVP) secretion. (6-12) AVP is the hormone primarily responsible for the regulation of urine production. In healthy adults, there is a diurnal release of AVP with peak blood concentrations occurring during the hours of sleep. (13) Blunting of the nocturnal phase of AVP secretion in subjects with nocturia would provide one plausible physiologic explanation for increased nocturnal urine production. However, not all patients with nocturia lack circadian AVP variation, and not all patients lacking circadian AVP variation have nocturia. (14) There are multiple physiologic changes in the mechanisms governing water and sodium regulation which can alter the diurnal rhythm of urine excretion. These include age-related declines in renal concentrating ability and plasma renin concentrations. (15) [008] Estimates of nocturia prevalence vary widely depending on the definition used, analytical method employed and population and region surveyed. (16-28) Despite these limitations, the literature strongly indicates that nocturia is a common and bothersome condition in males and females that increases in both prevalence and severity with age.

[009] One recent large survey, involving more than 19,000 males and females age 18 and older in five countries (Canada, Germany, Italy, Sweden, and the United Kingdom) and utilizing the ICS definition of nocturia (one or more times per night) showed that nocturia was the most prevalent lower urinary tract symptom - reported by 48.6% of men and 54.5% of women - and increased from 34 - 44% in individuals less than 39 years old to over 70% in those aged 60 years or more. Even with a higher threshold of two or more voids per night, the nocturia prevalence of 21 - 24% exceeded that of any other lower urinary tract symptom. (29)

[010] Older adults often cite nocturia as one of the most bothersome lower urinary tract symptoms. In a community-based survey of 423 men age 40 and older in the UK, 58 (14%) reported nocturia at least twice per night. And 67% of these reported that it was "at least a bit of a problem" - the second most bothersome symptom after frequency at least 9 times per day (92%), and more bothersome even than nocturnal incontinence (60%). (30) A community-based survey conducted in the USA including 720 subjects with nocturia showed that as little as one void per night was not only bothersome, but negatively affected health-related quality of life and sleep. For respondents with nocturia≥ 2 times per night, the impact on health related quality of life was similar to that of type 2 diabetes and greater than that of hypertension. (31) [011] The most pernicious effect of nocturia is not excessive voiding perse, but its impact on sleep quality and subsequent daytime function as a consequence of sleep disruption. There is a well established relationship between nocturia and sleep quality. A community-based Dutch survey of 1485 people age 50 and older reported that 25.3% reported disturbed sleep maintenance, for which nocturia was the most frequent cause (67.5%). (32)

[012] Asplund and Aberg investigated the relationship between sleep and nocturia in a sample of 3000 women and found that sleep deteriorated in association with increased nighttime voiding. Women with 3 or more voids per night reported four times more often that they lacked sleep and suffered from daytime sleepiness. (33)

[013] Insufficient sleep and daytime fatigue have been linked with depression, mood alteration and diminished quality of life. (34-36) A community-based Swedish survey of 203 working individuals with nocturia and 80 randomly selected controls showed that the group with nocturia had significantly lower levels of vitality and utility and greater impairment of work and activity as a consequence of sleep deprivation. (37)

[014] Nocturia is also associated with an increased incidence of falls during the nighttime hours. (38) Falls are a major health problem among older persons and are the leading cause of death from injuries in this age group. (39) In a study evaluating the risk of falls in ambulatory patients 65 years of age and older with nocturia, the odds ratio for falling increased from 1.46 for subjects with one nocturia event to 2.15 for subjects reporting more than three nocturia events per night. (40)

[015] Vasopressin is the primary physiologic determinant of free water excretion. It increases the water permeability of the luminal membrane of the renal cortical and medullary collecting ducts thereby promoting free water reabsorption and reducing urine production. As nocturia is the clinical consequence of excess nocturnal urine production relative to bladder capacity, reduction of nocturnal urine volume should logically result in fewer nighttime voiding episodes.

[016] Desmopressin is a synthetic analogue of the naturally occurring hormone 8-arginine vasopressin, with modifications including deamination of 1 -cysteine and substitution of L-arginine at position 8 by D-arginine. Desmopressin exhibits a high and specific antidiuretic effect as disclosed in U.S. Patent No. 3,497,491. The resulting molecule has an antidiuretic-to-vasopressor ratio 3000-fold greater than vasopressin and a longer duration of action. (41)

[017] Due to the bothersome nature and varied symptoms associated with nocturia, further investigation of desmopressin was warranted. Those investigations examined the efficacy and safety of desmopressin in broad populations. The result was surprising gender, age, and dose effects of desmopressin.

SUMMARY

[018] The present disclosure is directed to gender, age, and dose effects of desmopressin on reducing nocturnal voids, increasing an initial period of undisturbed sleep, and/or reducing nocturnal urine volume.

[019] For example, the present disclosure provides a method for increasing an initial period of undisturbed sleep in a patient in need thereof comprising: administering to the patient prior to bedtime an orodispersible dose of desmopressin of 10 pg, wherein the dose is measured as the free base of desmopressin and the dose taken over a treatment period increases the patient's initial period of undisturbed sleep.

[020] In further embodiments, the present disclosure is directed to a method for reducing nocturnal urine volume in a patient in need thereof comprising:

administering to the patient prior to bedtime an orodispersible dose of desmopressin of 10 pg, wherein the dose is measured as the free base of desmopressin and the dose taken over a treatment period reduces the patient's nocturnal urine volume.

[021] In still further embodiments, the present disclosure provides a method for reducing nocturnal voids in a female patient in need thereof comprising: administering to the patient prior to bedtime an orodispersible dose of desmopressin of 10 pg or 25 pg, wherein the dose is measured as the free base of desmopressin and the dose taken over a treatment period reduces the patient's nocturnal voids.

[022] In other embodiments, the present disclosure is directed to a method for increasing an initial period of undisturbed sleep in a female patient in need thereof comprising: administering to the patient prior to bedtime an orodispersible dose of desmopressin of 10 g or 25 g, wherein the dose is measured as the free base of desmopressin and the dose taken over a treatment period increases the patient's initial period of undisturbed sleep.

[023] In yet further embodiments, the present disclosure provides a method for reducing nocturnal urine volume in a female patient in need thereof comprising:

administering to the patient prior to bedtime an orodispersible dose of desmopressin of 10 pg or 25 pg, wherein the dose is measured as the free base of desmopressin and the dose taken over a treatment period reduces the patient's nocturnal urine volume.

[024] Further for example, the present disclosure is directed to a method for reducing nocturnal voids in a female patient above 50 years of age in need thereof comprising: administering to the patient prior to bedtime an orodispersible dose of desmopressin of 10 pg or 25 pg, wherein the dose is measured as the free base of desmopressin and the dose taken over a treatment period reduces the patient's nocturnal voids.

[025] In still further embodiments, the present disclosure provides a method for increasing an initial period of undisturbed sleep in a female patient above 50 years of age in need thereof comprising: administering to the patient prior to bedtime an orodispersible dose of desmopressin of 10 pg or 25 pg, wherein the dose is measured as the free base of desmopressin and the dose taken over a treatment period increases the patient's initial period of undisturbed sleep.

[026] In yet further embodiments, the present disclosure is directed to a method for reducing nocturnal urine volume in a female patient above 50 years of age in need thereof comprising: administering to the patient prior to bedtime an orodispersible dose of desmopressin of 10 pg or 25 pg, wherein the dose is measured as the free base of desmopressin and the dose taken over a treatment period reduces the patient's nocturnal urine volume.

[027] In other useful embodiments, the present disclosure provides a method for reducing nocturnal voids in a female patient above 65 years of age in need thereof comprising: administering to the patient prior to bedtime an orodispersible dose of desmopressin of 25 pg, wherein the dose is measured as the free base of

desmopressin and the dose taken over a treatment period reduces the patient's nocturnal voids.

[028] In further useful embodiments, the present disclosure is directed to a method for increasing an initial period of undisturbed sleep in a female patient above 65 years of age in need thereof comprising: administering to the patient prior to bedtime an orodispersible dose of desmopressin of 25 pg, wherein the dose is measured as the free base of desmopressin and the dose taken over a treatment period increases the patient's initial period of undisturbed sleep.

[029] In particular embodiments, the present disclosure provides a method for reducing nocturnal urine volume in a female patient above 65 years of age in need thereof comprising: administering to the patient prior to bedtime an orodispersible dose of desmopressin of 25 pg, wherein the dose is measured as the free base of

desmopressin and the dose taken over a treatment period reduces the patient's nocturnal urine volume.

[030] In some embodiments, the present disclosure is directed to a method for reducing nocturnal urine volume in a male patient in need thereof comprising:

measuring the patient's serum sodium level; administering to the patient, with a serum sodium level of at least 130 mmol/L, prior to bedtime an orodispersible dose of desmopressin of 100 pg, wherein the dose is measured as the free base of

desmopressin; measuring the patient's serum sodium level at a time interval after administration; continuing the administration of the dose of desmopressin with the patient having at least 130 mmol/L serum sodium level; wherein the dose administered over a treatment period reduces the patient's nocturnal urine volume.

[031] In another embodiment, the disclosure provides a method of treating nocturia by administering to a subject in need thereof a sublingual daily dose of about 10 μg ₁ 25 μg ₁ 50 μg, or 100 μg desmopressin (measured as the free base). The subject to be treated has an average of a least 0.5 fewer nocturnal urinary voids per night after 28 days of treatment with desmopressin.

[032] In a further embodiment, the present disclosure is directed to a method for reducing nocturnal voids in a patient in need thereof comprising: administering to the patient prior to bedtime an orodispersible dose of desmopressin ranging from 25 pg to 100 pg, wherein the dose is measured as the free base of desmopressin and the dose taken over a minimum treatment period reduces the patient's nocturnal voids compared to the patient's nocturnal voids before administration of the dose.

[033] In still yet another embodiment, the present disclosure provides for a method for improving a reduction in nocturnal voids in a patient in need thereof comprising: administering to the patient prior to bedtime an orodispersible dose of desmopressin ranging from 25 pg to 100 pg, wherein the dose is measured as the free base of desmopressin and the dose taken over a minimum treatment period reduces the patient's nocturnal voids compared to before administration and improves the reduction in nocturnal voids over the duration of the minimum treatment period.

[034] In a further embodiment, the present disclosure provides for a method for maintaining a reduction in nocturnal voids in a patient in need thereof comprising:

administering to the patient prior to bedtime an orodispersible dose of desmopressin of ranging from 25 pg to 100 pg, wherein the dose is measured as the free base of desmopressin and the dose is taken over a minimum treatment period reduces the patient's nocturnal voids compared to the patient's nocturnal voids before administration of the dose.

BRIEF DESCRIPTION OF DRAWINGS

[035] Figure 1 graphically illustrates the weekly change from baseline in mean number of nocturnal voids along with the corresponding p-values.

[036] Figure 2 graphically illustrates the mean observed and predicted change in nocturnal voids by gender and dose.

[037] Figure 3 graphically illustrates the decrease in total and nocturnal urine volume for the placebo, 10 pg, 25 pg, 50 pg, and 100 pg groups.

[038] Figure 4 graphically illustrates the mean observed and predicted change in nocturnal urine by gender and dose.

DESCRIPTION

[039] 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.

[040] Terms and Definitions

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

[042] 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.

[043] As used herein, the term "first sleep period" refers to the time elapsed from bedtime to either first void or morning arising. [044] 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 <130 mmol/L.

[045] The term "nocturnal enuresis" as used herein refers to a condition in which a person who has bladder control while awake urinates while asleep.

[046] 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%.

[047] As used herein, the term "nocturnal urine" refers to the total urine volume from 5 minutes after bedtime until rising in the morning, including the first void within 30 minutes of rising.

[048] The term "nocturnal void" as used herein refers to a void occurring from 5 minutes after bedtime until rising in the morning with the intention of getting up.

[049] The term "nocturia" refers to the complaint that an individual has to wake up at night one or more times to void.

[050] The term "overactive bladder" as used herein refers to urgency, with or without urge incontinence, usually accompanied by frequency and nocturia.

[051] The term "polydipsia" as used herein refers to excessive fluid

consumption.

[052] The term "urine osmolaity" as used herein refers to the concentration of electrolytes in urine. [053] The term "uroflometry" as used herein refers to a measurement of the rate of urine expelled from the bladder during bladder emptying. Flow rate is measured as mL/sec voided.

[054] The terms "administer," "administration" or "administering" as used herein refer to (1) providing, giving, dosing and/or prescribing by either a health practitioner or his authorized agent or under his direction desmopressin, and (2) putting into, taking or consuming by the patient or person himself or herself, desmopressin.

[055] List of Abbreviations

Abbreviations Meaning of abbreviations in document

AE Adverse Event

ITT Intention-To-Treat

LOCF Last-Observation-Carried-Forward

MED Minimum Effective Dose

OC Observed Cases

PP Per Protocol

SD Standard Deviation

SAE Serious Adverse Event

NQoL Nocturia Quality of Life Questionnaire

PSQI Pittsburgh Sleep Quality Index

SF Short Form

( ^j g Microgram

WebEZ Web Based Centralized Patient Randomization System

Melt Formulation

[056] Desmopressin Melt tablets contain desmopressin acetate in a freeze- dried presentation formulated with fish gelatin, mannitol and citric acid. The resulting oral Iyophilisate disintegrates instantaneously in the mouth without the need for water. An orodispersible pharmaceutical dosage form of desmopressin with good bioavailability is described in U.S. Patent Application No. 10/513,437 (U.S. Pub. No. 2005/0232997 A1), the contents of which are incorporated herein in their entirety. The Melt dosage form is preferably provided as a desmopressin acetate salt. The

desmopressin dosage may be expressed as free base, even though the desmopressin is actually supplied as the acetate salt. Except where otherwise indicated, the doses utilized in the present methods correspond to desmopressin free base even though the dosage form is a desmopressin acetate. Therefore, the 100 μg dose of desmopressin described herein is 100 μg of desmopressin free base, which corresponds to a proportionately higher weight value of desmopressin acetate (approximately 112.4 μg of desmopressin acetate for a desmopressin Melt preparation that is 89% w/w of desmopressin free base and for which the balance of 11 % w/w is acetate, water and impurities). Similarly, the 50 μg, 25 μg, and 10 μg dosages all represent the weights of desmopressin free base, with the corresponding weights of desmopressin acetate being proportionately higher. Accordingly, 0.1 mg of desmopressin acetate is equivalent to about 89 μg of desmopressin free base.

[057] The relative bioavailability between the tablet and melt formulations was investigated in an open-label, randomized crossover study in which 28 healthy subjects were administered 240 pg melt and 0.4 mg tablet (given as 2 x 0.2 mg tablets) separated by seven days. AUC, C _max , T _max and t _½ were similar, indicating that 0.1 mg tablet results in exposure similar to that of a 60 pg melt (equivalent to 67 μg of desmopressin acetate).

[058] EXAMPLE: Clinical Study [059] Objectives

[060] The primary objectives of Part I of this study (28-day efficacy) were: (1) to demonstrate the superiority of one or more doses of the Melt formulation of desmopressin to placebo in reducing the mean number of nocturnal voids in a broad population of adult patients with nocturia after 28 days of treatment; (2) to demonstrate the superiority of one or more doses of the Melt formulation of desmopressin to placebo in the proportion of subjects with >33% reduction from baseline in mean number of nocturnal voids after 28 days of treatment; and (3) treatment safety.

[061] The primary objectives of Part II of this study (extension study) were: (1) to demonstrate the durability of effect achieved in Part I of one or more doses of desmopressin Melt; and (2) treatment safety.

[062] The secondary objective of both Parts I and II was: to compare the effect of several doses of desmopressin Melt to placebo o sleep disturbance and quality of life.

[063] Overall Study Design

[064] This was a 2-part (Parts I and II), randomized, double-blind, placebo- controlled, parallel-group, multicenter study to investigate the efficacy and safety of 4 doses of a fast-dissolving ("Melt") formulation of desmopressin for the treatment of nocturia in adults. All treatments were administered orally once per night approximately 1 hour prior to bedtime; subjects were instructed to limit their fluid intake prior to drug self-administration. In Part I, subjects were randomly assigned to 1 of 5 treatment groups: placebo or desmopressin Melt 0 pg, 25 pg, 50 pg, or 100 pg. Randomization was to be stratified by age (<65, >65 years) and by the absence/presence of nocturnal polyuria, defined as a ratio of nighttime urine volume/24-hour urine volume >33%. To achieve the desired number of subjects within each stratum, enrollment of subjects in a particular stratum (age and/or presence/absence of nocturnal polyuria) could be halted. If this was necessary, all investigative sites were to be informed in writing at least 1 week in advance to stop screening in a population of subjects.

[065] A total of 750 subjects were planned to be enrolled, with approximately 150 subjects per treatment group. Part I of the study was conducted in 7 visits.

Screening (Visit 1) occurred within 21 days of dosing (Day 1 , Visit 2); subjects returned for follow-up visits on Days 4, 8, 15, 22, and 28 (end of Part I). Duration of treatment in Part I was 28 days.

[066] Immediately upon completion of Part I of the study, all subjects on active treatment continued into Part II on the same treatment for approximately 1 to 6 months. Subjects assigned to placebo in Part I were randomly assigned to 1 of the 4 active treatments in Part II. To ensure that the study remained fully blinded during the full extent of both Parts I and II, re-randomization of subjects assigned to placebo after 4 weeks of treatment was predetermined at the time of initial randomization.

[067] Subjects began Part II at the Final Visit for Part I (Day 28) and returned for follow-up visits on Days 4, 8, 15, 29, and every 4 weeks thereafter until the database was locked for Part I and the treatment groups were unblinded. The total treatment duration for each subject depended on when that subject was randomized in Part I and was estimated to be a minimum of 4 weeks and a maximum of 6 months.

[068] Upon completion of Part II of the study, subjects were given the option to participate in an open-label study with expected total treatment duration (double-blind extension plus open-label study) of at least 12 months (i.e., Part III). In Part III, subjects were assigned to the same treatment as in Part II, initially in a blinded manner.

Subjects were unblinded and the study became open label only when all subjects in Parts I and II remaining in the study had entered Part III. During Part III, 10 pg was identified as a sub-therapeutic dose based on efficacy data from Part I. As a

consequence, patients in the 10 pg treatment group were re-randomized (beginning Q4 2008) to one of the other treatment groups (i.e., 25 pg, 50 pg, or 100 pg).The total treatment duration was at least 12 months.

[069] A total of 508 patients entered the open-labeled extension (i.e., Part III). In total, 367 patients had≥ 1 year of treatment.

[070] Selection of Doses in Study

[071] A previous clinical program investigating the efficacy and safety of a Tablet formulation of desmopressin for nocturia utilized doses of 100 pg, 200 pg, and 400 pg. All 3 doses demonstrated a clear effect on pharmacodynamic and clinical endpoints. Although the use of a dose-titration scheme limits the interpretation of dose response, doses higher than 100 pg offered only a marginal improvement in efficacy.

[072] The dose relationship between the Tablet and Melt formulations was investigated in an open-label, randomized crossover study in which 28 healthy subjects were administered 240 pg Melt and 400 pg Tablet (given as 2x200 pg Tablets) separated by 7 days. AUC, C _max , T _max , and t _½ were similar, indicating that 100 pg Tablet provides an exposure similar to that of 60 pg Melt.

[073] The present study investigated dose levels substantially lower than those used in the Tablet study. While there are no data with the Melt formulation in the target population to guide dose selection for doses below 100 pg tablet/60 pg Melt, pharmacokinetic (PK) and pharmacodynamic (PD) studies have been conducted in water-loaded healthy subjects and water-loaded children 6 to 12 years of age with nocturnal enuresis. Based on data from these 2 studies, a model simulating PK and PD has been developed. If antidiuretic activity is defined in terms of duration of urine osmolality greater than 200 mOsm/kg, the model indicates that a dose of 10 pg Melt may potentially be subtherapeutic and doses of 25 pg to 100 pg should provide 2.75 to 8.5 hours of antidiuretic activity.

[074] Selection of Study Population: Inclusion Criteria

[075] Subjects who met the following inclusion criteria were eligible for the study: provided written informed consent prior to the performance of any study-related activity, defined as any procedure that would not have been performed during the normal management of the subject; and was a male or female subject, 18 years of age and older, with an average of >2 nocturnal voids per night determined via a 3-day frequency-volume chart during the screening period

[076] Exclusion Criteria

[077] The presence of any of the following excluded a subject from study enrollment:

[078] Genitourinary Tract Conditions

[079] Males:

[080] Clinical suspicion of bladder outlet obstruction and/or urine flow <5 mUsec. If medical history and/or physical examination suggested bladder outlet obstruction, uroflowmetry was to be performed to confirm the diagnosis. [081] Surgical treatment, including transurethral ablative treatments, for bladder outlet obstruction/benign prostatic hyperplasia (BPH) performed within the past 6 months.

[082] Females.

[083] Pregnancy; females of reproductive age were to document they were using a reliable method of contraception.

[084] Use of pessary for pelvic prolapse.

[085] Presence of unexplained pelvic mass.

[086] Males and Females:

[087] Clinical suspicion of urinary retention and/or post-void residual volume >150 mL; if medical history and/or physical examination suggested urinary retention, bladder ultrasound or catheterization was to be performed to confirm the diagnosis.

[088] Current or past urologic malignancies (e.g., bladder cancer, prostate cancer).

[089] Clinical evidence of current genitourinary tract pathology that could interfere with voiding.

[090] History of neurogenic detrusor activity (previously known as detrusor hyperreflexia).

[091] Systemic Medical Conditions

[092] Suspicion or evidence of cardiac failure.

[093] Uncontrolled hypertension.

[094] Uncontrolled diabetes mellitus. [095] Renal insufficiency; serum creatinine was to be within normal limits and estimated glomerular filtration rate (eGFR) was to be >60 mL/min.

[096] Hepatic and/or biliary disease; aspartate transaminase (AST) and/or alanine transaminase (ALT) were not to be >2 ^χ upper limit of normal (ULN) and total bilirubin was not to be >1.5 mg/dL

[097] Hyponatraemia; serum sodium level was to be within normal limits as defined by the Sponsor and central laboratory.

[098] Diabetes insipidus (urine output >40 mlJkg over 24 hours).

[099] Syndrome of inappropriate antidiuretic hormone secretion (SIADH).

[0100] Psychogenic or habitual polydipsia.

[0101] Obstructive sleep apnea requiring therapy.

[0102] Other

[0103] Known alcohol or substance abuse.

[0104] Work or lifestyle that potentially interfered with regular nighttime sleep (e.g., shift workers).

[0105] Previous desmopressin treatment for nocturia.

[0106] Any other medical condition, laboratory abnormality, psychiatric condition, mental incapacity, or language barrier that, in the judgment of the

Investigator, rendered the subject unsuitable for a clinical trial or impaired subject participation in the study.

[0107] Use of loop diuretics (furosemide, torsemide, ethacrynic acid). Other classes of diuretics (thiazides, triamterene, chlorthalidone, amiloride, indapamide) were permitted, either as monotherapy or combination therapy. Subjects using a diuretic were to be encouraged to take it in the morning, if medically feasible.

[0108] Use of any other investigational drug within 30 days of screening.

[0109] Discontinuation Criteria

[0110] Any subject with a serum sodium value of 125 mmol/L or less at any point during the study was to be withdrawn immediately and further evaluated and treated as necessary.

[0111] Subjects had the right to withdraw from the study at any time for any reason without providing justification. However, the Investigator was to take appropriate steps to ensure that withdrawal was accomplished in a safe manner. A subject could also be discontinued at the discretion of the Investigator or Sponsor because of safety concerns or if judged noncompliant with the study procedures to an extent that could affect the study results. The Investigator and the Sponsor were to agree on subject discontinuation prior to withdrawal, and unnecessary withdrawal of subjects was to be avoided.

[0112] Subjects discontinued from the study were to be scheduled for an End- of-Study (EoS) assessment as soon as possible after the decision to withdraw the subject had been made. For any discontinuation, the Investigator was to obtain all the required data and document the date of the premature withdrawal and the main reason in the electronic case report form (eCRF). If the reason for withdrawal was an adverse event (AE), the specific event or laboratory abnormality was to be recorded in the eCRF. The Investigator was to make a thorough effort to document the outcome.

Discontinued subjects were not replaced. [0113] Treatments Administered

[0114] Study drug was administered as an orally disintegrating tablet of desmopressin (desmopressin Melt) or placebo.

[0115] Subjects were randomly assigned to 1 of 5 fixed-dose treatment groups in Part I: placebo or desmopressin Melt 10 pg, 25 pg, 50 pg, or 100 pg. All treatments were administered orally once per night approximately 1 hour prior to bedtime. Subjects were instructed to place the tablet under their tongue, without water. Subjects were provided with sufficient study drug for the duration of Part I.

[0116] Study Endpoints

[0117] The primary endpoints for efficacy assessment were: (1 ) change in mean number of nocturnal voids from baseline evaluation to final visit (Day 28); and (2) proportion of subjects with >33% reduction in the mean number of nocturnal voids from baseline to final visit (Day 28). A further description and corresponding data directed to the second primary endpoint (i.e., portion of subjects with >33% reduction in the mean number of nocturnal voids) are not provided herein.

[0118] The secondary efficacy endpoints were: (1 ) durability of effect achieved in Part I; (2) change in initial period of undisturbed sleep, defined as the elapsed time in minutes from going to bed with the intention of sleeping to the time of awakening for the first nocturnal void; and (3) change in duration of total sleep time. Additional secondary endpoints were collected, e.g., change in nocturia-specific quality of life as assessed by scores on the International Consultation on Incontinence Modular Questionnaire - Noctuira and the Noctuira Quality of Life Questionnaire, change in quality of sleep as assessed by the global score of the Pittsburg Sleep Quality Index, and change in overall quality of life as assessed by the short form-12v2. A description of the additional secondary efficacy endpoints and their accompanying data are not provided herein.

[0119] Changes in urine volume from baseline to the end of Day 28 were also assessed and included herein.

[0120] Flow Chart

[0 21] A study flow chart, showing study assessments and procedures conducted at each study visit, are presented in Table 1 for Part I.

[0122] Table 1 - Study flow chart for Part I.

Serum sodium X X X X

Study drug accountability X X X X X

Dispense study drug for Part II (kit X number assigned via WebEZ)

EoS = End of Study; WebEZ = web-based centralized patient randomization system; BP = blood pressure; ICIQ-N = International Consultation on Incontinence questionnaire - Nocturia; PSQI = Pittsburgh Sleep Quality Index; NQoL = Nocturia Quality of Life; SF-12v2 = Short Form-12, version 2

a. Discontinued subjects were to complete an End-of-Study Visit as soon as possible after study discontinuation. b. Written informed consent was to be obtained prior to any study-related procedures. c. Collection of first night-time urine void prior to randomization visit.

d. Uroflometry was collected in males only if there was suspicion of obstruction; post

residual urine volume was measured using an ultrasound only if there was clinical suspicion of urinary retention.

e. Voiding diaries were completed for 3 consecutive 24-hour cycles; diaries for Weeks 1, 2, and 3 only required the "wake time" of the night-time void.

f. Actigraphy was used in a subset of subjects (at 6 study sites).

[0123] Disposition of Subjects

[0124] A total of 1412 subjects were screened for Part I of the study; 613

subjects were screening failures and 799 subjects were randomized to treatment. The most common recorded reasons for screening failure were renal insufficiency (15%) and not averaging≥2 nocturnal voids over the 3-day screening period (10%). A total of 710 (89%) subjects completed Part I of the study and 89 (1 %) subjects prematurely discontinued. Across treatment groups, 6% to 16% of subjects prematurely discontinued. The most common reasons for discontinuation overall were withdrawal of consent (4%), adverse event (2%), and lost to follow-up (2%).

[0125] Data Sets Analyzed

[0126] Of the 799 randomized subjects in Part I, 757 subjects who received at least 1 dose of study drug and had follow-up data were included in the intent to treat (ITT) analysis dataset. Overall, 10% of ITT subjects had a major protocol violation and were excluded from the per-protocol (PP) analysis dataset. Of the 682 PP subjects, 10% did not have both screening and final visit data on number of nocturnal voids and were excluded from the observed cases (OC) analysis dataset. All 799 randomized subjects received at least 1 dose of study drug (desmopressin or placebo) and had at least 1 safety assessment and, therefore, were included in the safety analysis dataset.

[0127] PRIMARY EFFICACY ENDPOINT

[0128] Number of Nocturnal Voids

[0129] The mean number of nocturnal voids decreased from baseline to Day 28 in all treatment groups, with greater decreases observed with increasing dose of desmopressin. The reduction in mean number of nocturnal voids, compared to placebo, was statistically significant for the 100 g (p<0.0001) and 50 ig (p=0.0207) groups.

[0130] The trend of greater decreases in mean number of nocturnal voids with increasing dose of desmopressin was evident in subjects stratified by age (<65 years, ≥65 years) and in subjects with nocturnal polyuria. Too few subjects (13 to 18 subjects per treatment group) did not have nocturnal polyuria to make meaningful comparisons. The reduction in mean number of nocturnal voids, compared to placebo, was statistically significant for the 100 g group for all 4 stratification factors and for the 50 pg group for subjects with nocturnal polyuria.

[0131] A summary of changes from baseline to the final visit in the number of nocturnal voids is presented for all groups (ITT population) in Table 2.

[0132] Table 2 - Change from baseline to final visit (Day 28) of nocturnal voids (ITT analysis dataset in Part I) for all groups.

n - population size; stddev - standard deviation; stderr - standard error; min - minimum; and max - maximum

[0133] Mean decreases in the number of nocturnal voids were observed by Day 8, with a trend for greater decreases with increasing desmopressin doses; these findings continued at Day 15 and Day 22. Notably, compared to placebo, statistically significant differences were observed for the 25 pg, 50 pg, and 100 pg doses on Day 8 and Day 15 of treatment, with significant differences for the 2 higher doses also on Day 22 and Day 28. Weekly change from baseline in mean number of nocturnal voids, along with p-values for each desmopressin Melt dose compared to placebo, is displayed in Figure 1. [0134] Among females, the reduction in mean number of nocturnal voids, compared to placebo, was statistically significant for the 100 pg (p<0.0001), 50 pg (p=0.0091), and 25 pg (p=0.0200) groups. Thus, among females, efficacy was demonstrated for the primary endpoint of nocturnal voids for all but the lowest dose of desmopressin.

[0135] A summary of changes from baseline to the final visit in the number of nocturnal voids is presented for all females, females over 50 years of age, and females over 65 years of age (ITT population) in Tables 3, 4 and 5.

[0136] Table 3 - Change from baseline to final visit (Day 28) of nocturnal voids (ITT analysis dataset in Part I) for all females.

n - population size; stddev - standard deviation; stderr - standard error; min - minimum; and max - maximum

[0137] Although not statistically significant for the 10 pg group but statistically significant for the 25 pg group, there was a decrease observed in the median number of nocturnal voids identified in Table 3 for all females. For example, the 10 pg and 25 pg groups exhibited at least 1.0 fewer nocturnal urinary voids per night on desmopression treatment compared to baseline before treatment. The placebo exhibited only 0.67 fewer nocturnal urinary voids per night compared to baseline.

[0138] Table 4 - Change from baseline to final visit (Day 28) of nocturnal voids (ITT analysis dataset in Part I) for females over 50 years of age.

minimum; and max - maximum

[0139] Although not statistically significant for the 10 pg group but statistically significant for the 25 pg group, there was a decrease observed in the median number of nocturnal voids identified in Table 4 for females over 50 years of age. For example, the 10 pg and 25 pg groups exhibited at least 1.0 fewer nocturnal urinary voids per night on desmopression treatment compared to baseline before treatment. The placebo exhibited only 0.67 fewer nocturnal urinary voids per night compared to baseline.

[0140] Table 5 - Change from baseline to final visit (Day 28) of nocturnal voids (ITT analysis dataset in Part I) for females over 65 years of age.

Dose n mean stddev stderr min median max Placebo 21 -0.51 0.73 0.16 -2.33 -0.33 0.67

10 ug 25 -0.93 1.07 0.21 -4.33 -0.67 0.33

25 ug 22 -1.27 0.99 0.21 -2.67 -1.67 1.00

50 ug 20 -0.97 0.95 0.21 -2.33 -1.00 1.33

100 ug 25 -1.00 1.18 0.24 -3.00 -1.00 1.00

Total 113 -0.94 1.02 0.10 -4.33 -1.00 1.33 n - population size; stddev - standard deviation; stderr - standard error; min - minimum; and max - maximum

[0141] Similarly to the other female groups, there was a decrease observed in the median number of nocturnal voids identified in Table 5 for females over 65 years of age at the 25 [ig group. For example, the 25 pg group exhibited at least 1.67 fewer nocturnal urinary voids per night on desmopressin treatment compared to baseline before treatment. The placebo exhibited only 0.33 fewer nocturnal urinary voids per night compared to baseline.

[0142] Among males, statistically significant differences from placebo were observed for the 100 pg group in the reduction in mean number of nocturnal voids (p=0.0049).

[0143] A summary of the changes from baseline to the final visit in the number of nocturnal voids is presented for all males and all males with monitoring (ITT population) in Tables 6 and 7.

[0144] Table 6 - Change from baseline to final visit (Day 28) of nocturnal voids (ITT analysis dataset in Part I) for all males. Dose n mean stddev stderr min median max

Placebo 90 -0.84 1.09 0.12 -4.00 -1.00 1.67

10 ug 82 -0.54 0.99 0.11 -3.00 -0.67 2.33

25 ug 87 -0.83 1.15 0.12 -3.67 -0.67 2.33

50 ug 77 -1.13 1.30 0.15 -5.00 -1.00 1.33

100 ug 80 -1.38 1.28 0.14 -4.33 -1.33 4.33

Total 416 -0.94 1.19 0.06 -5.00 -1.00 4.33 n - population size; stddev - standard deviation; stderr - standard error; min - minimum; and max - maximum

[0145] Table 7 - Change from baseline to final visit (Day 28) of nocturnal voids (ITT analysis dataset in Part I) for all males with monitoring.

n - population size; stddev - standard deviation; stderr - standard error; min - minimum; and max - maximum

[0146] The differences among males and females in the change in number of nocturnal voids is illustrated in Figure 2. In Figure 2, the mean observed (full line) and predicted (broken line) change in number of voids by gender and dose demonstrate that the 10 pg and 25 pg groups for females exhibit a larger decrease in nocturnal voids compared to the 10 pg and 25 pg groups for males. The side-by-side comparison in Figure 2 highlights the gender and dose differences without the requirement of statistical significance.

[0147] Based on these gender differences, the minimum effective dose (MED) for females is 25 pg and the MED for males is 100 pg.

[0148] Long Term Data - Nocturnal Voids

[0149] At one year (Part III), the mean decrease in nocturnal voids per night was 1.4, 1.77, and 2.11 (for 25 pg, 50 pg, and 100 pg, respectively) based on all eligible subjects. The mean decreases in nocturnal voids demonstrate that the decrease observed for the respective concentrations at Day 28 (i.e., Part I) are maintained over a longer treatment period (e.g., 52 weeks) and in some instances, are be even improved. A summary of the changes from baseline is presented for all eligible subjects. With respect to this particular data for Part III, "all eligible subjects" means those subjects that continued through Parts I, II, and III of the study on the same dose (i.e., re-randomized placebo subjects have been excluded) and completed the 1 year diary.

[0150] Applicants note that statistical significance cannot be demonstrated for the Part III data on nocturnal voids, as the placebo group was not maintained for Part III. However, based on the data below, the additional decreases in the number of voids can be characterized as clinically significant. As used here, "clinically significant" means a minimum worthwhile effect. [0151] A summary of changes from baseline to day 28 and to week 52 in the number of nocturnal voids is present for all eligible groups in Tables A, B, and C for the 25 pg, 50 pg, and 100 pg doses of desmopressin.

[0152] Table A - Baseline at day 0 and changes from baseline nocturnal voids for all eligible subjects at the 25 pg dosage.

n - population size; stddev - standard deviation; min - minimum; and max - maximum

[0153] Table B - Baseline at day 0 and changes from baseline for all eligible subjects at the 50 pg dosage.

n - population size; stddev - standard deviation; min - minimum; and max - maximum [0154] Table C - Baseline at day 0 and changes from baseline for all eligible subjects at the 100 pg dosage.

n - population size; stddev - standard deviation; min - minimum; and max - maximum

[0155] Although not statistically significant, the change from baseline to Week 52 in comparison to the change of baseline to day 28 demonstrates that for all eligible subjects, the decrease in frequency of nocturnal voids can be maintained and/or improved over a longer treatment period in a clinically significant manner.

[0156] Among females, the reduction in mean number of nocturnal voids from baseline to week 52 maintained or improved, particularly at the 25 pg dose. A summary of changes from baseline to week 52 in the number of nocturnal voids is presented for all females in Tables D-F for the 25 pg, 50 pg, and 100 pg doses of desmopressin.

[0157] Table D - Baseline at day 0 and changes from baseline for all eligible female subjects at the 25 pg dosage. n Mean Std Dev Min Max

Day 0 38 3.23 1.31 2.00 8.67

Day 28 38 -1.26 1.06 -3.33 0.67 Week 8 32 -1.51 0.83 -3.00 0

Week 12 29 -1.66 0.98 -3.00 0.67

Week 20 22 -1.68 0.96 -3.00 0.67

Week 28 27 -1.86 1.18 -4.33 0.33

Week 52 38 -1.75 1.16 -4.67 2.00 n - population size; stddev - standard deviation; min - minimum; and max - maximum

[0158] Table E - Baseline at day 0 and changes from baseline of nocturnal voids for all eligible female subjects at the 50 [ig dosage.

n - population size; stddev - standard deviation; min - minimum; and max - maximum

[0159] Table F - Baseline at day 0 and changes from baseline of nocturnal voids for all eligible female subjects at the 100 [ig dosage. n Mean Std Dev Min Max

Day 0 37 3.08 1.12 2.00 7.00

Day 28 37 -1.50 1.22 -5.00 1.00

Week 8 32 -1.69 1.27 -5.00 0.33

Week 12 27 -1.79 1.23 -5.00 0.33

Week 20 22 -1.98 1.29 -5.33 0 Week 28 26 -1.75 1.01 -4.67 -0.33

Week 52 37 -2.11 1.35 -6.33 0.67 n - population size; stddev - standard deviation; min - minimum; and max - maximum

[0160] Among males, decreases in mean nocturnal voids from baseline to week

52 were observed. A summary of the changes from baseline to week 52 is presented for all eligible male subjects in Tables G-l.

[0161] Table G - Baseline at day 0 and changes from baseline of nocturnal voids for all eligible male subjects at the 25 pg dosage.

n - population size; stddev - standard deviation; min - minimum; and max - maximum

[0162] Table H - Baseline at day 0 and changes from baseline of nocturnal voids for all eligible male subjects at the 50 g dosage. n Mean Std Dev Min Max

Day 0 45 3.59 1.25 2.00 7.00

Day 28 45 -1.16 1.23 -5.00 1.00

Week 8 32 -1.31 1.04 -3.67 1.33

Week 12 28 -1.30 1.11 -3.67 1.00 Week 20 30 -1.73 1.13 -4.00 1.00

Week 28 25 -1.28 1.37 -5.00 1.00

Week 52 45 -1.69 1.58 -6.67 0.33 n - population size; stddev - standard deviation; min - minimum; and max - maximum

[0163] Table I - Baseline at day 0 and changes from baseline of nocturnal voids for all eligible male subjects at the 100 g dosage.

n - population size; stddev - standard deviation; min - minimum; and max - maximum

[0164] Tables J-L summarize the data for all subjects with or without an assessment at week 52.

[0165] Table J - Baseline at day 0 and changes from baseline of nocturnal voids for all subjects at the 25 pg dosage.

Std

n Mean Minimum Maximum

Dev

Day 0 158 3.38 1.35 2.00 8.67

Day 28 158 -0.96 1.12 -3.67 2.33

Week 100 -1.31 1.16 -4.67 2.67

Week 12 85 -1.42 1.23 -5.00 2.00 Week 20 60 -1.61 1.16 -6.00 1.67

Week 28 87 -1.39 1.14 -4.33 1.33

Week 52 86 -1.41 1.26 -4.67 2.33 n - population size; stddev - standard deviation; min - minimum; and max - maximum

[0166] Table K - Baseline at day 0 and changes from baseline of nocturnal voids for all subjects at the 50 pg dosage.

n - population size; stddev - standard deviation; min - minimum; and max - maximum

[0167] Table L - Baseline at day 0 and changes from baseline of nocturnal voids for all subjects at the 100 pg dosage. n Mean Std Minimum Maximum

Dev

Day 0 160 3.22 1.06 2.00 7.33

Day 28 160 -1.31 1.23 -5.00 4.33

Week 8 104 -1.47 1.08 -5.00 0.67

Week 12 81 -1.73 1.04 -5.00 0.33

Week 20 64 -1.86 1.08 -5.33 0 Week 61 -1.80 0.90 -4.67 0.67

Week 52 73 -2.11 1.14 -6.33 0.67

n - population size; stddev - standard deviation; min - minimum; and max - maximum

[0168] SECONDARY EFFICACY ENDPOINTS

[0169] The secondary efficacy variables were changes from baseline in duration of initial period of undisturbed sleep, duration of total sleep time, and changes in nocturnal urine volume. As noted, the additional secondary efficacy variables data collected (i.e., global (overall) scores of the NQoL, PSQI, and SF-12v2, and scores of the ICIQ-N) are not presented herein.

[0 70] Duration of Initial Period of Undisturbed Sleep

[0171] The most pernicious effect of nocturia is not excessive voiding per se, but its impact on sleep quality and subsequent daytime function as a consequence of sleep disruption. The duration of the initial period of undisturbed sleep increased from baseline to Day 28 in all treatment groups, with greater increases observed with increasing dose of desmopressin. Mean increases in initial sleep duration were 83, 85, and 107 minutes in the 25 pg, 50 pg, and 100 pg groups, respectively. Subjects treated with 25 pg and 50 pg desmopressin had a median increase in their initial period of sleep of approximately 1 hour while subjects treated with the 100 pg dose had a median increase in initial sleep duration of approximately 1½ hours. The 95% confidence intervals for the mean difference from placebo in change from baseline did not include zero for the 25 pg, 50 pg, and 100 pg groups, indicating statistically significant treatment group differences. [0172] A summary of changes from baseline to the final visit in initial period of undisturbed sleep is presented for all groups (ITT population) in Table 8.

[0173] Table 8 - Change from baseline to final visit (Day 28) in duration of initial period of undisturbed sleep (ITT analysis dataset in Part I) for all groups.

n - population size; stddev - standard deviation; stderr - standard error; min - minimum; and max - maximum

[0174] Although not statistically significant, an increase in the initial period of undisturbed sleep is evident for the 10 pg group as compared to placebo based on median values identified in Table 8 for all groups. For example, the 10 group exhibited a median increase of 51 minutes compared to baseline before treatment. The placebo exhibited only a median increase of 42 minutes compared to baseline. Taking into consideration a 5% range from the median increase for the 10 pg group, increases in an initial period of undisturbed sleep range from 48 minutes to 54 minutes compared to baseline before treatment.

[0175] A summary of changes from baseline to the final visit in initial period of undisturbed sleep is presented for all females, females over 50 years of age, and females over 65 years of age (ITT population) in Tables 9, 10 and 11. [0176] Table 9 - Change from baseline to final visit (Day 28) in duration of initial period of undisturbed sleep (ITT analysis dataset in Part I) for all females.

minimum; and max - maximum

[0177] Although not statistically significant, an increase in the initial period of undisturbed sleep is evident for the 10 pg and 25 pg groups as compared to placebo based on median values identified in Table 9 for all female patients. For example, the 10 pg group exhibited a median increase of 46 minutes and the 25 pg group exhibited a median increase of 95 minutes compared to baseline before treatment. The placebo exhibited only a median increase of 12 minutes compared to baseline. Taking into consideration a 20% range from the median increase for the 10 pg and 25 pg groups, increases in an initial period of undisturbed sleep ranges from 37 minutes to 114 minutes, such as from 37 minutes to 55 minutes for the 10 pg group and from 76 minutes to 114 minutes for the 25 pg group compared to baseline for all females. [0178] Table 10 - Change from baseline to final visit (Day 28) in duration of initial period of undisturbed sleep (ITT analysis dataset in Part I) for females over 50 years of age.

n - population size; stddev - standard deviation; stderr - standard error; min - minimum; and max - maximum

[0179] Although not statistically significant, an increase in the initial period of undisturbed sleep is evident for the 10 pg and 25 pg groups as compared to placebo based on median values identified in Table 0 for female patients over 50 years of age. For example, the 10 pg group exhibited a median increase of 27 minutes and the 25 pg group exhibited a median increase of 96 minutes compared to baseline before treatment. The placebo exhibited only a median increase of 11 minutes compared to baseline. Taking into consideration a 20% range from the median increase for the 10 pg and 25 pg groups, increases in an initial period of undisturbed sleep ranges from 22 minutes to 15 minutes, such as from 22 minutes to 32 minutes for the 10 pg group and from 77 minutes to 115 minutes for the 25 pg group, compared to baseline before treatment for females over 50 years of age. [0180] Table 11 - Change from baseline to final visit (Day 28) in duration of initial period of undisturbed sleep (ITT analysis dataset in Part I) for females over 65 years of age.

minimum; and max - maximum

[0181] Although not statistically significant, an increase in the initial period of undisturbed sleep is evident for the 25 pg group as compared to placebo based on median values identified in Table 11 for female patients over 65 years of age. For example, the 25 pg group exhibited a median increase of 113 minutes compared to baseline before treatment. The placebo exhibited only a median increase of 52 minutes compared to baseline. Taking into consideration a 20% range from the median increase for the 25 pg group, increases in an initial period of undisturbed sleep range from 90 minutes to 136 minutes, such as from 102 minutes to 124 minutes, compared to baseline before treatment for females over 65 years of age. [0182] A summary of changes from baseline to the final visit in initial period of undisturbed sleep is presented for all males and all males with monitoring (ITT population) in Tables 12 and 13.

[0183] Table 12 - Change from baseline to final visit (Day 28) in duration of initial period of undisturbed sleep (ITT analysis dataset in Part I) for all males.

n - population size; stddev - standard deviation; stderr - standard error; min - minimum; and max - maximum

[0184] Table 13 - Change from baseline to final visit (Day 28) in duration of initial period of undisturbed sleep (ITT analysis dataset in Part I) for all males with monitoring.

Dose n mean stddev stderr min median max

Placebo 70 44 85 10 -273 48 285

10 ug 60 54 107 14 -145 59 370

25 ug 62 57 87 11 -104 54 259

50 ug 45 64 89 13 -165 59 291

100 ug 52 108 103 14 -152 116 363

Total 289 64 96 6 -273 58 370 n - population size; stddev - standard deviation; stderr - standard error; min - minimum; and max - maximum

[0185] Duration of Total Sleep Time

[0186] Total sleep time increased in all treatment groups in Part I; however, no pattern was observed by dose of desmopressin. Based on F-tests of effects, computed overall sleep duration and reported overall sleep duration were statistically significant predictors of change from baseline to Day 28 in total sleep time (p<0.0001).

[0187] A summary of change from baseline to Day 28 in total sleep time is presented by treatment group in Table 14.

[0188] Table 14 - Change from baseline to final visit (Day 28) in total sleep time (Part I).

Total Sleep Time Placebo 10 pg 25 Mg 50 Mg loo g (min) (N=156) (N=155) (N= 52) (N=148) (N=146)

Calculated Sleep

Time

Baseline (N=156) (N=155) (N=152) (N=148) (N=146)

Mean (SD) 399 (97.0) 397 (92.2) 397 (90.3) 404 (95.8) 414 (85.0)

Median 410 402 412 415 418

Minimum, (15, 732) (135, 720) (95, 577) (20, 577) (72, 638) maximum

Change from (N=138) (ISM 37) (N=142) (N=138) (N=133)

Baseline 31.4 (89.22) 9.7 (91.40) 19.7 (71.67) 24.2 (79.60) 9.7 (77.33) Mean (SD) 19.5 10.0 15.3 14.2 12.0 Median (-167, 420) (-332, 282) (-191 , 318) (-235, 218) (-300, 227) Minimum,

maximum

Reported Sleep

Time

Baseline (N=156) (N=155) (N=152) (N=148) (N=146)

Mean (SD) 403 (83.7) 411 (72.8) 401 (77.8) 403 (83.7) 413 (81.3)

Median 408 400 410 409 410

Minimum, (135, 625) (190, 613) (77, 555) (100, 580) (100, 674) maximum

Change from (N=139) (N=137) (N=141) (N=138) (N=133)

Baseline 24.6 (80.66) 7.8 (58.55) 15.9 (53.92) 24.9 (72.21) 19.0 Mean (SD) 20.3 10.0 10.0 20.0 (68.94) Median (-135, 525) (-130, 163) (-1 3, 228) (-168, 293) 20.0 Minimum, (-160, 197) maximum

[0189] Change in Urine Volume

[0190] Pharmacodynamic studies indicate that desmopressin has a very pronounced antidiuretic effect. Nocturnal urine volume decreased in all treatment groups, with greater decreases observed with increasing desmopressin dose. For change from baseline to Day 28 in nocturnal urine volume, based on F-tests of effects, treatment (p<0.0001), age (p=0.0067), and baseline nocturnal urine volume (p<0.0001) were statistically significant predictors for change from baseline. The 95% confidence intervals for the mean difference from placebo in change from baseline did not include zero for the 25 pg, 50 pg, and 100 pg groups, indicating statistically significant treatment group differences.

[0191] Similarly, total urine volume, which included both day and nocturnal voids, decreased in all treatment groups, with greater decreases observed with increasing desmopressin dose. In the 50 pg group, a slight mean increase in urine output occurred during the day and, as a result, the nocturnal mean urine reduction was greater than the total mean urine reduction.

[0192] As shown in Figure 3, the majority of the decrease in total urine volume was a decrease in nocturnal volume. The decreases in nocturnal urine volume for the 25 pg, 50 pg, and 100 pg groups were statistically significant.

[0193] A summary of changes from baseline to the final visit in of nocturnal urine volume is presented for all groups (ITT population) in Table 15.

[0194] Table 15 - Change from baseline to final visit (Day 28) of nocturnal urine volume (ITT analysis dataset in Part I) for all groups.

Dose n mean stddev stderr min median max

Placebo 140 -109 246 21 -817 -94 800

10 ug 137 -164 277 24 -983 -150 568

25 ug 144 -224 264 22 -1 ,084 -233 567

50 ug 138 -272 296 25 -1,017 -233 717

100 ug 135 -312 275 24 -1 ,238 -283 408 Total 694 -216 281 11 -1 ,238 -200 800 n - population size; stddev - standard deviation; stderr - standard error; min - minimum; and max - maximum

[0195] Although not statistically significant, a decrease in nocturnal urine volume is evident for the 10 pg group as compared to placebo based on median decreases identified in Table 15 for all groups. For example, the 10 pg group exhibited a median value decrease of 150 ml compared to baseline before treatment. The placebo exhibited only a median decrease of 94 ml compared to baseline. Taking into consideration a 20% range from the median decrease for the 10 pg group, decreases in nocturnal urine volume include at least 20 ml and for example, range from 120 ml to 180 ml, compared to baseline before treatment for all groups.

[0196] A summary of changes from baseline to the final visit of nocturnal urine volume is presented for all females, females over 50 years of age, and females over 65 years of age (ITT population) in Tables 16, 17 and 18.

[0197] Table 16 - Change from baseline to final visit (Day 28) of nocturnal urine volume (ITT analysis dataset in Part I) for all females.

Dose n mean stddev stderr min median max

Placebo 60 -86 278 36 -817 -56 800

10 ug 66 -207 292 36 -983 -179 538

25 ug 61 -307 276 35 -1 ,084 -298 292

50 ug 66 -257 282 35 -1 ,017 -204 717

100 ug 60 -321 239 31 -933 -283 25 Total 313 -236 285 16 -1 ,084 -217 800 n - population size; stddev - standard deviation; stderr - standard error; min - minimum; and max - maximum

[0198] Although not statistically significant, a decrease in nocturnal urine volume is evident for the 10 ig and 25 pg groups as compared to placebo based on median decreases identified in Table 16 for all females. For example, the 10 \ig group exhibited a median decrease of 179 ml and the 25 pg group exhibited a median decrease of 298 ml compared to baseline before treatment. The placebo exhibited only a median decrease of 56 ml compared to baseline. Taking into consideration a 20% range from the median decreases for the 10 yig and 25 g groups, decreases in nocturnal urine volume include at least 143 ml and for example, range from 143 ml to 358 ml, such as from 143 ml to 215 ml for the 10 g group and from 238 ml to 358 ml for the 25 g group, compared to baseline before treatment for all females.

[0199] Table 17 - Change from baseline to final visit (Day 28) of nocturnal urine volume (ITT analysis dataset in Part I) for females over 50 years of age.

Dose n mean stddev stderr min median max

Placebo 44 -102 242 36 -817 -56 268

10 ug 45 -197 319 48 -983 -150 538

25 ug 46 -356 281 41 -1 ,084 -383 292

50 ug 52 -249 289 40 -1 ,017 -196 717

100 ug 45 -317 252 38 -933 -275 25

Total 232 -245 290 19 -1,084 -217 717 n - population size; stddev - standard deviation; stderr - standard error; min - minimum; and max - maximum

[0200] Although not statistically significant, a decrease in nocturnal urine volume is evident for the 10 pg and 25 pg groups as compared to placebo based on median decreases identified in Table 17 for females over 50 years of age. For example, the 10 pg group exhibited a median decrease of 150 ml and the 25 pg group exhibited a median decrease of 383 ml compared to baseline before treatment. The placebo exhibited a median decrease of 56 ml compared to baseline. Taking into consideration a 20% range from the median decreases for the 10 pg and 25 pg groups, decreases in nocturnal urine volume include at least 120 ml and for example, range from 120 ml to 460 ml, such as from 120 ml to 180 ml for the 10 pg group and from 306 ml to 460 ml for the 25 pg group, compared to baseline before treatment for females over 50 years of age.

[0201] Table 8 - Change from baseline to final visit (Day 28) of nocturnal urine volume (ITT analysis dataset in Part I) for females over 65 years of age.

Dose n mean stddev stderr min median max

Placebo 20 -90 170 38 -557 -47 133

10 ug 22 -91 302 64 -742 -54 538

25 ug 19 -372 270 62 -867 -383 25

50 ug 20 -208 323 72 -703 -203 717

100 ug 23 -323 261 54 -817 -285 25

Total 104 -216 290 28 -867 -171 717 n - population size; stddev - standard deviation; stderr - standard error; min - minimum; and max - maximum

[0202] Although not statistically significant, a decrease in nocturnal urine volume is evident for the 25 pg group as compared to placebo based on median decreases identified in Table 18 for females over 65 years of age. For example, the 25 pg group exhibited a median decrease of 383 ml compared to the placebo median decrease of 47 ml compared to baseline before treatment. Taking into consideration a 20% range from the median decrease for the 25 pg group, decreases in nocturnal urine volume include at least 21 1 ml and for example, range from 238 ml to 290 ml, compared to baseline before treatment for females over 65 years of age.

[0203] A summary of changes from baseline to the final visit of nocturnal urine volume is presented for all males and all males with monitoring (ITT population) in Tables 19 and 20.

[0204] Table 19 - Change from baseline to final visit (Day 28) of nocturnal urine volume (ITT analysis dataset in Part I) for all males.

Dose n mean stddev stderr min median max

Placebo 80 -125 219 25 -727 -111 583

10 ug 71 -125 257 30 -750 -1 17 568

25 ug 83 -162 238 26 -873 -200 567

50 ug 72 -286 309 36 -984 -246 422

100 ug 75 -306 302 35 -1 ,238 -270 408

Total 381 -199 276 14 -1 ,238 -192 583 n - population size; stddev - standard deviation; stderr - standard error; min - minimum; and max - maximum

[0205] Table 20 - Change from baseline to final visit (Day 28) of nocturnal urine volume (ITT analysis dataset in Part I) for all males with monitoring.

n - population size; stddev - standard deviation; stderr - standard error; min - minimum; and max - maximum

[0206] From Table 20, a decrease in nocturnal urine volume is evident for the 100 ig group as compared to placebo based on median decreases from baseline. For example, the 100 \ig group exhibited a median decrease of 264 ml compared to baseline before treatment. The placebo exhibited only a median decrease of 111 ml compared to baseline. Taking into consideration a 20% range from the median decrease for the 100 g group, decreases in nocturnal urine volume include at least 211 ml and for example, range from 211 ml to 317 ml, such as from 238 ml to 290 ml, compared to baseline before treatment for males with monitoring.

[0207] The differences among males and females in the change in nocturnal urine volume is illustrated in Figure 4. In Figure 4, the mean observed (full line) and predicted (broken line) change in nocturnal urine volume demonstrate the greater sensitivity to lower doses (i.e., 10 pg and 25 pg groups) in females than males. The side-by-side comparison in Figure 4 highlights the gender and dose differences without the requirement of statistical significance.

[0208] Statistical/Analytical Issues - Handling of Dropouts or Missing Data

[0209] Missing values concerning number of nocturnal voids at Day 8, Day 15, Day 22, and Day 28 in Part I were imputed using last observation carried forward (LOCF). Missing values concerning sleep disturbance and urine volume (for average 24-hour urine volume and average nocturnal urine volume) were not imputed.

[0210] Drug Dose. Drug Concentration and Relationships to Response

[0211] Four doses of desmopressin (10 g, 25 pg, 50 pg, and 100 pg) were included in this study. Both the primary endpoint of the number of nocturnal voids generally demonstrated an increase in efficacy with increasing dose of desmopressin. An additional analysis of the primary efficacy endpoint was performed by gender and demonstrated gender differences in response. Among females, efficacy was

demonstrated for the 25 pg, 50 pg, and 100 pg doses of desmopressin for the primary endpoint. Among males, the 100 pg desmopressin dose was superior to placebo for the primary endpoint. Based on these gender differences, the MED for females is 25 pg and for males is 100 pg.

[0212] Efficacy Conclusions

[0213] Four doses of desmopressin (10 pg, 25 pg, 50 pg, and 100 pg) were compared to placebo in this study for the primary endpoint in Part I: change in the mean number of nocturnal voids from baseline to final visit (Day 28). [0214] The mean number of nocturnal voids decreased from baseline to Day 28 in all treatment groups, with greater decreases observed with increasing dose of desmopressin. The reduction in mean number of nocturnal voids, compared to placebo, was statistically significant for the 100 pg and 50 pg groups. The trend of greater decreases in mean number of nocturnal voids with increasing dose of desmopressin was evident in subjects stratified by age (<65 years, >65 years) and in subjects with nocturnal polyuria. Too few subjects did not have nocturnal polyuria to make

meaningful comparisons. The reduction in mean number of nocturnal voids, compared to placebo, was statistically significant for the 100 pg group for all 4 stratification factors and for the 50 pg group for subjects with nocturnal polyuria. When decreases in mean number of nocturnal voids were examined by week of treatment, statistically significant differences, compared to placebo, were observed for the 25 pg, 50 pg, and 100 pg doses on Day 8 and Day 15 of treatment, with significant differences for the 2 higher doses also on Day 22 and Day 28.

[0215] An additional analysis of the primary efficacy endpoint was performed by gender, and a gender difference in response was observed. Among females, the reduction in mean number of nocturnal voids was statistically significantly superior to placebo for the 100 pg, 50 pg, and 25 pg groups. Among males, statistically significant differences from placebo were observed for the primary endpoint for the 100 pg group. Based on these gender differences, the MED for females is 25 pg and the MED for males is 100 pg.

[0216] Nocturnal urine volume, as well as total urine volume, decreased in all treatment groups, with greater decreases observed with increasing desmopressin dose. Based on 95% confidence intervals that did not include zero, the decreases in nocturnal urine volume for the 25 pg, 50 pg, and 100 pg groups were statistically significant.

[0217] The secondary efficacy endpoint of change from baseline to final visit (Day 28) in duration of initial period of undisturbed sleep also demonstrated greater increases with increasing dose of desmopressin. Subjects treated with 25 pg and 50 pg had a median increase in their initial period of sleep of approximately 1 hour while subjects treated with the 100 pg dose had a median increase in initial sleep duration of approximately 1 ½ hours; the 95% confidence intervals for the mean difference from placebo indicated statistically significant differences for the 25 pg, 50 pg, and 100 pg groups.

[0218] In summary, the efficacy of 100 pg desmopressin was demonstrated superior to placebo for the primary endpoint overall; for the primary endpoint, among males and among females; proportions of subjects with >50% and >75% reductions in the mean number of nocturnal voids; change from baseline to final visit (Day 28) in duration of the initial period of undisturbed sleep; and reductions in nocturnal urine volume. The efficacy of 50 pg desmopressin was superior to placebo for change from baseline to Day 28 in the mean number of nocturnal voids; for the primary endpoint among females; duration of the initial period of undisturbed sleep; and reductions in nocturnal urine volume. In addition, numerical superiority was observed for 50 pg desmopressin compared to placebo for the proportion of subjects with >33% reductions (53% vs. 47%), >50% reductions (28% vs. 20%), and >75% reductions (10% vs. 5%) in the mean number of nocturnal voids on Day 28. The 25 pg dose was superior to placebo for the primary endpoint among females; in reducing the mean number of nocturnal voids; change from baseline to Day 28 in duration of the initial period of undisturbed sleep; and reductions in nocturnal urine volume. The 10 pg dose did not demonstrate statistically superiority over placebo for the primary or secondary efficacy endpoint. A gender difference in response was observed. For the primary endpoint, superiority to placebo was demonstrated for the 25 pg, 50 pg, and 100 pg doses among females and for the 100 pg dose among males.

[0219] Results of Study CS29 demonstrated that the 100 pg dose was clearly efficacious, while the 10 pg dose can be considered subtherapeutic for the primary efficacy parameter for the overall study population. Based on the observed gender differences, the MED for females is 25 pg and the MED for males is 100 pg.

[0220] At 1 year, the mean decrease in nocturnal voids was 1.4, 1.77, and 2.11 (for 25 pg, 50 pg, and 100 pg, respectively) based on all eligible subjects.

[0221] Adverse Events Leading to Discontinuation: Hyponatraemia and Serum Sodium Monitoring

[0222] The reported event of hyponatraemia, defined as serum sodium <130 mmol/L, was an adverse event of special interest. A total of 34 (4%) subjects developed hyponatraemia during Part I. There was essentially no difference in the occurrence of hyponatraemia between placebo and the 10 pg and 25 pg groups;

however, the incidence of serum sodium <130 mmol/L rose from 1.3% in the 25 pg group to 7.0% in the 50 pg group and to 11.3% in the 100 pg group. Hyponatraemia tended to occur early in treatment, usually during the first week, and was more common in subjects≥65 years of age. [0223] Since hyponatremia is a potentially serious adverse event associated with daily doses of desmopressin, serum sodium was monitored throughout the study in all subjects. Based on the results of Study CS29, the following sodium monitoring criteria were applied to the CS29 data.

[0224] In subjects below 50 years of age:

Baseline serum sodium level > 135 mmol/L.

[0225] In subjects 50 years of age and above:

Baseline serum sodium level≥ 135 mmol/L

Day 4 serum sodium level > 135 mmol/L

Day 28 serum sodium level≥ 135 mmol/L.

[0226] Subjects who did not meet these criteria would be removed. Without monitoring, serum sodium levels below 125 mmol/L occurred in 3 subjects each in the 50 pg and 100 pg groups on Day 4 and 1 subject in each of these groups on Day 8. It should be remembered that serum sodium monitoring occurred the day after the evening dose of study drug.

[0227] Based on these findings, serum sodium monitoring at Day 4 and Day 28 is recommended in males older than 65 years of age at 100 pg. The serum sodium levels at Day 4 and Day 28 should be≥ 135 mmol/L. In males below 65 years of age who are treated at 100 pg, no further monitoring appears to be warranted. In female subjects who are treated at 25 pg, no further monitoring appears to be warranted.

[0228] Dosing

[0229] Results of Study CS29 demonstrated that the 10 pg dose was considered a subtherapeutic dose for the primary efficacy parameters when looking at the overall population. While the 100 pg dose was clearly efficacious, the risk of hyponatraemia was greater than with the lower doses of desmopressin. Although not as effective as the 100 pg dose, the benefit:risk ratio favored the 25 pg and 50 pg doses. The 25 pg dose was clearly less likely to cause hyponatraemia than the 50 pg and 100 pg doses and was statistically significantly superior to placebo in the primary efficacy endpoint among females. Among males, the 100 pg desmopressin dose was statistically significantly superior to placebo for the primary endpoint. Based on these gender differences, the MED for females is 25 pg and the MED for males is 100 pg.

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