Comparative Trial to Investigate the Dose-Response of 4 Different Dose Levels of Minirin Melt and Placebo

Study Overview
=================
Brief Summary
-----------------
This is a multi-centre, randomised, placebo-controlled, double-blind, parallel-group comparative trial to be conducted in nocturia patients. The trial is designed to characterize the dose-response relationship of Minirin (desmopressin) Melt in order to establish correct dose recommendations in the target patient population. In particular, the trial is designed to link the duration of action to the clinical endpoint. Furthermore, the trial is designed to describe the safety of four different dose levels of desmopressin.

Official Title
-----------------
A Multi-centre, Double-blind, Randomised, Placebo-controlled, Parallel-group, Comparative Trial to Investigate the Dose-Response of 4 Different Dose Levels of Minirin Melt and Placebo in Water-loaded Male and Female Japanese Nocturia Patients (Single Dose), and to Study the Efficacy of 4 Different Dose Levels of Minirin Melt and Placebo After 28 Days of Dosing (Multiple Doses)

Conditions
-----------------
Nocturia

Intervention / Treatment
-----------------
* Drug: Desmopressin
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Given written informed consent prior to any trial-related activity is performed Aged 55-75 years Mean number of nocturnal voids of at least two per night Reached post-menopause (applicable to females only) Exclusion Criteria: Evidence of bladder outlet obstruction (BOO); or a urine flow of less than 5 mL/s (applicable to males only) A surgical treatment for BOO or prostatic hyperplasia within the past 6 months (applicable to males only) Showing symptoms of any of the following diseases and having a mean number of nocturnal voids exceeding four per night: Benign prostatic hyperplasia, overactive bladder, interstitial cystitis, severe stress urinary incontinence Psychosomatic or habitual polydipsia Urinary retention; or a post void residual volume in excess of 150 mL A history or complication of urologic malignancy (e.g. bladder cancer or prostate cancer) Complication of genito-urinary pathology (e.g. infection, stone, or neoplasia) Complication of neurogenic detrusor activity Complication or suspicion of heart failure Uncontrolled hypertension Uncontrolled diabetes mellitus Complication of hepatobiliary disease Abnormal serum creatinine level Complication of hyponatraemia, or serum sodium level <135 mEq/L Central or nephrogenic diabetes insipidus (CDI or NDI) Syndrome of inappropriate antidiuretic hormone (SIADH) Obstructive sleep apnea Alcohol dependency or drug abuse A job or lifestyle that may interfere with regular night-time sleep Previous desmopressin treatment Treatment with another investigational product within the past 3 months A need for treatment with a prohibited concomitant drug for a complication or other problem A mental condition, the lack of decision-making ability, dementia or a speech handicap Any other reason that the Investigator believes inappropriate

Ages Eligible for Study
-----------------
Minimum Age: 55 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Desmopressin 10µg<br>Study period 1: single dose of desmopressin 10µg. Study period 2: daily doses of desmopressin 10µg taken before bedtime for 28 days. | Drug: Desmopressin<br>* Desmopressin oral lyophilisate melt tablet, in either the 10, 25, 50, or 100 μg dosage, for sublingual administration<br>* Other names: Minirin Melt;|
| Experimental: Desmopressin 25µg<br>Study period 1: single dose of desmopressin 25µg. Study period 2: daily doses of desmopressin 25µg taken before bedtime for 28 days. | Drug: Desmopressin<br>* Desmopressin oral lyophilisate melt tablet, in either the 10, 25, 50, or 100 μg dosage, for sublingual administration<br>* Other names: Minirin Melt;|
| Experimental: Desmopressin 50µg<br>Study period 1: single dose of desmopressin 50µg. Study period 2: daily doses of desmopressin 50µg taken before bedtime for 28 days. | Drug: Desmopressin<br>* Desmopressin oral lyophilisate melt tablet, in either the 10, 25, 50, or 100 μg dosage, for sublingual administration<br>* Other names: Minirin Melt;|
| Experimental: Desmopressin 100µg<br>Study period 1: single dose of desmopressin 100µg. Study period 2: daily doses of desmopressin 100µg taken before bedtime for 28 days. | Drug: Desmopressin<br>* Desmopressin oral lyophilisate melt tablet, in either the 10, 25, 50, or 100 μg dosage, for sublingual administration<br>* Other names: Minirin Melt;|
| Placebo Comparator: Placebo<br>Study period 1: single dose of placebo. Study period 2: daily doses of placebo taken before bedtime for 28 days. | Drug: Placebo<br>* Placebo melt tablet for sublingual administration<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Action Defined as the Time With Urine Osmolality Above 200 mOsm/kg - Period 1 | Participants were water-loaded to suppress the endogenous release of vasopressin, thus all antidiuretic activity was generated by desmopressin only. Water-loading was initiated 2 hours before dosing on Day 1. Urine volume was registered and samples for osmolality check were collected every 30 minutes as long as there was an antidiuretic action defined as a urine production <0.12 mL/kg/min. The hydration should have lasted until end of action, defined as when the urine production returned to >0.12 mL/kg/min, but no longer than 12 hours. | Day 1 | 
| Change From Baseline in Number of Nocturnal Voids After 28 Days of Treatment - Period 2 | Records of nocturia and sleep over three consecutive days per week were kept in voiding-sleep diaries by study participants. The average number of nocturnal voids of the 3 days recorded in the last week of the study (between study days 25-32) was compared to average baseline readings. | 3 days between study days -6 to 0 (Baseline), and days 25 to 32 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Urine Osmolality Curve (AUCosm) | Area under the urine osmolality curve, from dose administration to end of action (AUCosm). | Day 1 | 
| Area Under the Urine Production Curve (AUCurine Prod) | Area under the urine production curve, from dose administration to end of action (AUCurine prod) | Day 1 | 
| Time When Urine Production <0.12 ml/kg/Min | Urine volume was registered and samples for osmolality check were collected every 30 minutes as long as there was an antidiuretic action defined as a urine production <0.12 mL/kg/min. The hydration due to water-loading should have lasted until end of action, defined as when the urine production returned to >0.12 mL/kg/min, but no longer than 12 hours. | Day 1 | 
| Change From Baseline in Duration of First Period of Undisturbed Sleep After 28 Days of Treatment - Period 2 | Duration of first period of undisturbed sleep is defined as the length of time from initial sleep to first awakening. Records of nocturia and sleep over three consecutive days per week were kept in voiding-sleep diaries by study participants. The average length of first period of undisturbed sleep of the 3 days recorded in the last week of the study (between study days 25-32) was compared to average baseline readings. | 3 days between study days -6 to 0 (Baseline), and days 25 to 32 | 
| Change From Baseline in Total Sleep Time at Approximately Day 32 | Total sleep time is defined as the time spent asleep from initial sleep to final awakening. Records of nocturia and sleep over three consecutive days per week were kept in voiding-sleep diaries by study participants. The average of the total time asleep of the 3 days recorded in the last week of the study (between study days 25-32) was compared to average baseline readings. | 3 days between study days -6 to 0 (Baseline), and days 25 to 32 | 
| Change From Baseline in Number of Daytime Voids at Approximately Day 32 | Number of daytime voids was recorded over three consecutive days per week in diaries kept by study participants. The average number of daytime voids of the 3 days recorded in the last week of the study (between study days 25-32) was compared to the average baseline readings. | 3 days between study days -6 to 0 (Baseline), and days 25 to 32 | 
| Change From Baseline in Number of 24-hour Urine Voids at Approximately Day 32 | Number of voids in 24 hours was recorded over three consecutive days per week in diaries kept by study participants. The average number of 24-hour voids of the 3 days recorded in the last week of the study (between study days 25-32) was compared to the average baseline readings. | 3 days between study days -6 to 0 (Baseline), and days 25 to 32 | 
| Change From Baseline in Nocturnal Urine Volume at Approximately Day 32 | Nocturnal urine volume was recorded over three consecutive days per week in diaries kept by study participants. The average nocturnal urine volume of the 3 days recorded in the last week of the study (between study days 25-32) was compared to the average baseline readings. | 3 days between study days -6 to 0 (Baseline), and days 25 to 32 | 
| Change From Baseline in 24-Hour Urine Volume at Approximately Day 32 | Twenty-four hour urine volume was recorded over three consecutive days per week in diaries kept by study participants. The average 24-hour urine volume of the 3 days recorded in the last week of the study (between study days 25-32) was compared to the average baseline readings. | 3 days between study days -6 to 0 (Baseline), and days 25 to 32 | 
| Change From Baseline in 24-Hour Urine Production Per Body Weight at Approximately Day 32 | Twenty-four hour urine volume was recorded over three consecutive days per week in diaries kept by study participants. Urine volume per body weight was calculated. The average 24-hour urine volume per kg of body weight of the 3 days recorded in the last week of the study (between study days 25-32) was compared to the average baseline readings. | 3 days between study days -6 to 0 (Baseline), and days 25 to 32 | 
| Change From Baseline in Nocturnal Polyuria Index at Approximately Day 32 | Nocturnal polyuria index is defined as a proportion of nocturnal urine volume to the 24-hour urine volume. Urine volume and time of day of those voids was recorded over three consecutive days per week in diaries kept by study participants. The average nocturnal polyuria index of the 3 days recorded in the last week of the study (between study days 25-32) was compared to the average baseline readings. | 3 days between study days -6 to 0 (Baseline), and days 25 to 32 | 
| Change From Baseline in Nocturia-Related Quality of Life Based on Evaluation Provided by Nocturia Quality of Life Questionnaire (N-QoL) at Approximately Day 32 | N-QoL assesses the impact of nocturia on quality of life (QoL) and treatment outcomes. N-QoL is a self-administered questionnaire with 13 items using scales of 0 = no negative impact to QoL to the upper number = signficant negative impact to QoL. The sleep/energy domain consists of 7 questions with a scale of 0 to 28. The bother/concern domain consists of 5 questions for a scale of 0 to 20. The 13th question is an overall assessment scored from 0 to 10. The Total Score includes all 13 questions with a scale of 0 (no negative impact to QoL) to 58 (significant negative impact to QoL). | Approximately Day 4 (start of period 2) and Day 32 | 
| Change From Baseline in Sleep Related Quality of Life Based on the Global Score of the Pittsburgh Sleep Quality Index (PSQI) at Approximately Day 32 | The Global Score of the Pittsburgh Sleep Quality Index (PSQI) is comprised of Questions 2-9 with a total scale of 0 (no difficulty sleeping) to 21 (severe difficulty). The change in Global Score is Global Score at the end of period 2 (day 32) - Global Score at the start of Period 2 (day 4). A negative change indicates an improvement in quality of life. | Approximately Day 4 (start of period 2) and Day 32 | 
| Participant Counts of Minimum Observed Serum Sodium Levels During the Second Treatment Period (Days 4-32) | Serum sodium levels were monitored throughout the trial as part of the clinical chemistry panel. If the value was ≤125 mEq/L, the participant was to be withdrawn from the trial and treatment stopped immediately. This outcome reports participants' lowest recorded serum sodium levels during the second treatment period. | Days 4- 32 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
nocturia, bladder function