Investigation of the Superiority Effect of Orally Disintegrating Desmopressin Tablets to Placebo in Terms of Night Voids Reduction in Nocturia Adult Male Patients

Study Overview
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Brief Summary
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The purpose of this trial was to confirm/establish long-term safety and efficacy of desmopressin orally disintegrating tablets at dose levels of 50 μg and 75 μg and to further evaluate the safety of an efficacious higher dose level of 100 μg in males with nocturia.

Official Title
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A Multi-centre, Randomised, Double-blind, Placebo-controlled, Parallel-group Trial With an Open-label Extension to Demonstrate the Efficacy and Safety of Desmopressin Orally Disintegrating Tablets for the Treatment of Nocturia in Adult Males

Conditions
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Nocturia

Intervention / Treatment
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* Drug: Desmopressin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent prior to performance of any trial-related activity Male sex 18 years of age or older At least 2 voids every night in a consecutive 3-day period during the screening period based on the patient diary. 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 Chronic prostatitis/chronic pelvic pain syndrome Suspicion of bladder outlet obstruction (BOO) or a urine flow of less than 5 mL/s as confirmed by uroflowmetry performed after suspicion of BOO Surgical treatment, including transurethral resection, for BOO or benign prostatic hyperplasia within the past 6 months Urinary retention or a post void residual volume in excess of 250 mL as confirmed by bladder ultrasound performed after suspicion of urinary retention Habitual or psychogenic fluid intake resulting in a urine production exceeding 40 mL/kg/24 hours Central or nephrogenic diabetes insipidus. Syndrome of inappropriate anti-diuretic hormone. Current or a history of urologic malignancies e.g. urothelium, prostate, or kidney 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, i.e. loop diuretics (furosemide, torsemide, ethacrynic acid) and any other investigational drug 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
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Desmopressin 50 μg Double-Blind / 100 μg Open-Label<br>Participants took 1 orally disintegrating tablet of desmopressin 50 μg every night approximately 1 hour prior to bedtime for the entire duration of the 3-month double-blind treatment period. Participants completing the double-blind period were switched to desmopressin 100 μg for the 1-month open-label extension period. | Drug: Desmopressin<br> <br> * Other names: Nocturin®;|
| Experimental: Desmopressin 75 μg Double-Blind / 100 μg Open-Label<br>Participants took 1 orally disintegrating tablet of desmopressin 75 μg every night approximately 1 hour prior to bedtime for the entire duration of the 3-month double-blind treatment period. Participants completing the double-blind period were switched to desmopressin 100 μg for the 1-month open-label extension period. | Drug: Desmopressin<br> <br> * Other names: Nocturin®;|
| Placebo Comparator: Placebo Double-Blind / Desmopressin 100 μg Open-Label<br>Participants took 1 orally disintegrating tablet of placebo every night approximately 1 hour prior to bedtime for the entire duration of the 3-month double-blind treatment period. Participants completing the double-blind period were switched to desmopressin 100 μg for the 1-month open-label extension period. | Drug: Desmopressin<br> <br> * Other names: Nocturin®;Drug: Placebo<br> <br> |

What is the study measuring?
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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 outcome. Superiority to placebo was to be simultaneously demonstrated on the 2 co-primary outcomes in a step-down approach from highest (75 μg) to lowest dose (50 μg), thereby controlling the family-wise error rate at the 5% nominal significance level. | Day 1 (Baseline), Week 1, Months 1, 2, 3 (3-month double-blind 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 outcome. Superiority to placebo was to be simultaneously demonstrated on the 2 co-primary endpoints in a step-down approach from highest (75 μg) to lowest dose (50 μg), thereby controlling the family-wise error rate at the 5% nominal significance level. | Day 1 (Baseline), Week 1, Months 1, 2, 3 (3-month double-blind treatment period) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Mean Number of Nocturnal Voids at Month 3 | Comparison of the mean number of nocturnal voids at baseline and at the 3-month visit. The number of nocturnal voids was the average over 3 consecutive 24-hour periods prior to the relevant visits 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. The active treatment groups were compared to placebo using a step-down approach from highest dose (75 µg) to lowest dose (50 µg). | 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. The active treatment groups were compared to placebo using a step-down approach from highest dose (75 µg) to lowest dose (50 µg). | 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 the case where there was no nocturnal void. The first morning void was not counted as a 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. The active treatment groups were compared to placebo using a step-down approach from highest dose (75 µg) to lowest dose (50 µg). | 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. The active treatment groups were compared to placebo using a step-down approach from highest dose (75 µg) to lowest dose (50 µg). | 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. The active treatment groups were compared to placebo using a step-down approach from highest dose (75 µg) to lowest dose (50 µg). | Day 1 (Baseline), Month 3 | 
| Summary of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Double-Blind Period | A TEAE was any adverse event (AE) occurring after start of treatment and within the time of residual drug effect, i.e., within 1 day for desmopressin. An adverse drug reaction (ADR) was any AE assessed by the investigator as possibly or probably related to study drug. | From Day 1 through Month 3 (double-blind period) | 
| Summary of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Open-Label Period | A TEAE was any adverse event (AE) occurring after start of treatment and within the time of residual drug effect, i.e., within 1 day for desmopressin. An adverse drug reaction (ADR) was any AE assessed by the investigator as possibly or probably related to study drug. | Month 1 of open-label period (Month 4 of treatment) | 
| Minimum Post-Treatment Serum Sodium Levels in the Double-Blind Period | Serum sodium levels were monitored at each study visit 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 through Month 3 (double-blind period) | 
| Minimum Post-Treatment Serum Sodium Levels in the Open-Label Period | Serum sodium levels were monitored at each study visit 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. | Month 1 of open-label period (Month 4 of treatment) |