Investigation of the Superiority Effect of Desmopressin to Placebo in Terms of Night Voids Reduction in Nocturia Adult Female Patients

Study Overview
=================
Brief Summary
-----------------
A multicenter, randomized, double-blind, placebo-controlled, parallel-group trial to investigate the safety and efficacy of desmopressin oral melt tablets against placebo during 3 months of treatment in adult females with nocturia.

Official Title
-----------------
A Multi-centre, Randomised, Double-blind, Placebo-controlled, Parallel-group Trial to Demonstrate the Efficacy and Safety of Desmopressin Orally Disintegrating Tablet for the Treatment of Nocturia in Adult Females

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

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


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Written informed consent prior to performance of any trial-related activity Female sex 18 years of age or older At least 2 voids every night in a consecutive 3-day period during the screening period Exclusion Criteria: Evidence of severe daytime voiding dysfunction defined as: Urge urinary incontinence (more than 1 episode/day in the 3-day diary period) Urgency (more than 1 episode/day in the 3-day diary period) Frequency (more than 8 daytime voids/day in the 3-day diary period) Interstitial cystitis Urinary retention or a post void residual volume in excess of 150 mL as confirmed by bladder ultrasound performed after suspicion of urinary retention Habitual or psychogenic polydipsia (fluid intake resulting in a urine production exceeding 40 mL/kg/24 hours) Central or nephrogenic diabetes insipidus Syndrome of inappropriate anti-diuretic hormone secretion Current or a history of urologic malignancies e.g. bladder cancer Genitourinary tract pathology e.g., infection or stone in the bladder and urethra causing symptoms Neurogenic detrusor activity (detrusor overactivity). Suspicion or evidence of cardiac failure Uncontrolled hypertension Uncontrolled diabetes mellitus Hyponatraemia: Serum sodium level must be within normal limits Renal insufficiency: Serum creatinine must be within normal limits and estimated glomerular filtration rate must be more than or equal to 50 mL/min Hepatic and/or biliary diseases: Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) levels must not be more than twice the upper limit of normal range. Total bilirubin level must not be more than 1.5 mg/dL History of obstructive sleep apnea Previous desmopressin treatment for nocturia Treatment with another investigational product within 3 months prior to screening Concomitant treatment with any prohibited medication e.g., loop diuretics (furosemide, torsemide, ethacrynic acid) and any other investigational drug Pregnancy, breastfeeding, or a plan to become pregnant during the period of the clinical trial. Subjects of reproductive age must have documentation of a reliable method of contraception. All pre-and perimenopausal subjects have to perform pregnancy tests. Amenorrhea of more than 12 months' duration based on the reported date of the last menstrual period is sufficient documentation of post-menopausal status and does not require a pregnancy test Known alcohol or substance abuse Work or lifestyle that may interfere with regular nighttime sleep e.g., shift workers Any other medical condition, laboratory abnormality, psychiatric condition, mental incapacity, or language barrier that, in the judgment of the Investigator, would impair participation in the trial

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

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 25 μg<br>Participants took 1 orally disintegrating tablet of desmopressin 25 μg every night approximately 1 hour before bedtime for the entire duration of the 3-month treatment period. | Drug: Desmopressin<br> <br> * Other names: Nocturin®;|
| Placebo Comparator: Placebo<br>Participants took 1 orally disintegrating tablet of placebo every night approximately 1 hour before bedtime for the entire duration of the 3-month treatment period. | Drug: Placebo<br> <br> |

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Mean Number of Nocturnal Voids Averaged Over a 3-Month Period | The number of nocturnal voids was the average over 3 consecutive 24-hour periods prior to Day 1 and prior to the during-treatment visits (Week 1, Months 1, 2, 3) as recorded in participant diaries. The first morning void was not counted as a nocturnal void. Change from baseline values for Week 1, and Months 1, 2 and 3 are reported below. Comparison of the mean number of nocturnal voids at baseline and over a 3-month treatment period (obtained by longitudinal analysis of Week 1, and Months 1, 2 and 3) are reported in the statistical analysis. This was the first co-primary endpoint. The trial was to be declared positive only if the 25 μg desmopressin group had a statistically significant positive effect as compared to placebo on both co-primary endpoints. | Day 1 (Baseline); Week 1, Months 1, 2, 3 (3-month treatment period) | 
| Adjusted Probability of Participants Achieving a >33% Reduction From Baseline in Number of Nocturnal Voids for All During-Treatment Visits up to Month 3 | Probability of participants achieving 33% responder status during 3 months of treatment employed a longitudinal analysis assessing nocturnal void information captured in the 3-day diary. A 33% responder was defined as a participant with a decrease of at least 33% in the mean number of nocturnal voids relative to baseline. The number of nocturnal voids was the average over 3 consecutive 24-hour periods prior to Day 1 and prior to the during treatment visits (Week 1, Months 1, 2, 3) as recorded in participant diaries. The first morning void was not counted as a nocturnal void. This was the second co-primary endpoint. The trial was to be declared positive only if the 25 μg desmopressin group had a statistically significant positive effect as compared to placebo on both co-primary endpoints. | Day 1 (Baseline); Week 1, Months 1, 2, 3 (3-month treatment period) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Mean Number of Nocturnal Voids at Month 3 | The number of nocturnal voids was the average over 3 consecutive 24-hour periods prior to Day 1 and prior to the during-treatment visits (Month 3 for this outcome) as recorded in participant diaries. The first morning void was not counted as a nocturnal void. Secondary efficacy outcomes (#3-7) used a hierarchical step-down approach in the order listed. | Day 1 (Baseline), Month 3 | 
| Adjusted Probability of Participants Achieving a >33% Reduction From Baseline in Number of Nocturnal Voids at Month 3 | Probability of participants achieving 33% responder status at Month 3 employed a longitudinal analysis assessing nocturnal void information captured in the 3-day diary. A 33% responder was defined as a participant with a decrease of at least 33% in the mean number of nocturnal voids relative to baseline. The number of nocturnal voids was the average over 3 consecutive 24-hour periods prior to Day 1 and prior to the Month 3 visit as recorded in participant diaries. The first morning void was not counted as a nocturnal void. The secondary efficacy outcomes (#3-7) used a hierarchical step-down approach in the order listed. | Day 1 (Baseline), Month 3 | 
| Change From Baseline in Mean Time to First Nocturnal Void at Month 3 | The time to first void was defined as the time from going to bed with the intention of sleeping until first nocturnal void or until waking in the morning in cases where there was no nocturnal void. The time to first void was derived from the sleep and voiding diary. The mean time to first void was calculated as the average over 3 consecutive 24-hour periods prior to the Month 3 visit. The secondary efficacy outcomes (#3-7) used a hierarchical step-down approach in the order listed. | Day 1 (Baseline), Month 3 | 
| Change From Baseline in Nocturnal Urine Volume at Month 3 | The nocturnal urine volume was derived from the 3-day urine volume diary. The nocturnal urine volume included the volume of the first morning void. Mean urine volumes were calculated as the average over 3 consecutive 24-hour periods prior to the Month 3 visit. The secondary efficacy outcomes (#3-7) used a hierarchical step-down approach in the order listed. | Day 1 (Baseline), Month 3 | 
| Change From Baseline in 24-Hour Urine Volume at Month 3 | Twenty-four hour urine volume was derived from the 3-day urine volume diary. Mean urine volumes were calculated as the average over 3 consecutive 24-hour periods prior to the Month 3 visit. The secondary efficacy outcomes (#3-7) used a hierarchical step-down approach in the order listed. | Day 1 (Baseline), Month 3 | 
| Summary of Participants With Treatment-Emergent Adverse Events (TEAEs) | A TEAE was any adverse event occurring after start of treatment and within the time of residual drug effect, i.e., within 1 day of the last dose of desmopressin. An adverse drug reaction (ADR) was any AE assessed by the Investigator as possibly/probably related to study drug. | Day 1 up to 3 months | 
| Minimum Post-Treatment Serum Sodium Levels | Serum sodium levels were monitored since hyponatremia is a potential serious adverse event associated with daily doses of desmopressin. The serum sodium level must have been within the normal reference range at the Screening Visit for the participant to be eligible for enrollment. A participant was to be withdrawn from the trial if the serum sodium level was <=125 mmol/L at any time. | Day 1 up to 3 months |