Study Investigating the Impact Burden of Nocturia Using the Nocturia Impact Diary

Study Overview
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Brief Summary
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The purpose of this study is to assess psychometric properties (reliability and validity) of the Nocturia Impact (NI) diary. To assess the association between reduction of number of nocturnal voids and the mean changes in NI scores (sensitivity of the NI total score to change in nocturia). To assess which NI diary items account for the main difference in change in total NI score in treatment versus placebo.

Official Title
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A Double-blind, Randomized, Placebo-controlled Study Investigating the Impact Burden of Nocturia Using the Nocturia Impact Diary

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 study-related activity 18 years of age (at the time of written consent) or older Previous participation in FE992026 CS40 or FE992026 CS41 with a completion ≥ 30 days prior to Screening. The subject should have responded to active treatment during FE992026 CS40 or FE992026 CS41 or if he/she received placebo during these two studies he/she should have been a non-responder. At least two nocturnal voids every night in two consecutive 3-day periods during the screening period (as determined by the two night-time voiding diaries dispensed at Visit 1 and collected at Visit 2) Exclusion Criteria: Chronic prostatitis (males)/chronic pelvic pain syndrome (CPPS) Suspicion of bladder outlet obstruction (BOO) or a urine flow of < 5 mL/s as confirmed by uroflowmetry performed after suspicion of BOO Surgical treatment, including transurethral resection, for BOO or benign prostatic hyperplasia (males) within the past six months Urinary retention or a post void residual volume > 150 mL for females and > 250 mL for males as confirmed by bladder ultrasound performed after suspicion of urinary retention Central or nephrogenic diabetes insipidus Syndrome of inappropriate antidiuretic hormone Current or a history of urologic malignancies e.g. bladder cancer Genito-urinary 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 Chronic prostatitis (males)/chronic pelvic pain syndrome (CPPS) 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 ≥ 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 > 1.5 mg/dL History of obstructive sleep apnea Treatment with another investigational product (except desmopressin) within three months prior to screening and throughout the study Concomitant treatment with loop diuretics (furosemide, torsemide, ethacrynic acid) Pregnancy, breastfeeding, or an intention of becoming pregnant during the period of the clinical study. Female subjects of reproductive age must have documentation of a reliable method of contraception. All pre-and perimenopausal female subjects have to perform pregnancy tests. Amenorrhea of > 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 night-time sleep e.g. shiftworkers 23. Any other medical condition, laboratory abnormality, psychiatric condition, mental incapacity, or language barrier which, in the judgment of the Investigator, would impair participation in the study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Female - Desmopressin 25 μg<br>Female participants took 1 tablet of 25 μg every night, approximately 1 hour prior to bedtime (with the intention to sleep), for a period of 1 month. | Drug: Desmopressin<br>* Desmopressin orally disintegrating tablets. Female participants took a 25 μg tablet and male participants took a 75 μg tablet one hour prior to bedtime for one month.<br>* Other names: Nocturin®;|
| Placebo Comparator: Female - Placebo<br>Female participants took 1 tablet of placebo every night, approximately 1 hour prior to bedtime (with the intention to sleep), for a period of 1 month. | Drug: Placebo<br>* Placebo to match the 25 μg tablet of active drug taken by female participants or the 75 μg tablet taken by males. One placebo tablet taken one hour prior to bedtime for one month.<br>|
| Experimental: Male - Desmopressin 75 μg<br>Male participants took 1 tablet 75 μg every night, approximately 1 hour prior to bedtime (with the intention to sleep), for a period of 1 month. | Drug: Desmopressin<br>* Desmopressin orally disintegrating tablets. Female participants took a 25 μg tablet and male participants took a 75 μg tablet one hour prior to bedtime for one month.<br>* Other names: Nocturin®;|
| Placebo Comparator: Male - Placebo<br>Male participants took 1 tablet of placebo every night, approximately 1 hour prior to bedtime (with the intention to sleep), for a period of 1 month. | Drug: Placebo<br>* Placebo to match the 25 μg tablet of active drug taken by female participants or the 75 μg tablet taken by males. One placebo tablet taken one hour prior to bedtime for one month.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Pearson Correlation Coefficient Between Change From Baseline to Month 1 in Number of Nocturnal Voids and Change From Baseline to Month 1 in Nocturia Impact (NI) Diary Total Score | This outcome is a measure of sensitivity of the NI Diary to change in nocturia. The NI Diary is a 12-item instrument consisting of 11 core items and an overall impact question (Q12). Responses are scored from 0 (no impact) to 4 (highest impact); a lowering of score equals a decrease in impact caused by nocturia. The NI total score is the sum of the 11 core items scores. The NI total score was analyzable only if all 11 items (Q1-Q11) had non-missing responses. Otherwise, it was defined as missing. Missing values were not imputed. The average over the 3-day diary period prior to baseline (Day 1) and Month 1 was used for the overall impact score. The correlation was estimated using Fisher's z transformation, i.e. the NI total score was based on a standardized scale from 0 (lowest impact) to 100 (highest impact). Corresponding adjusted partial correlation coefficients were based on adjustments for mean number of Baseline voids, Baseline NI total score, age, and gender. | Day 1 (Baseline), Month 1 | 
| Difference in Mean Change From Baseline to Month 1 in Nocturia Impact (NI) Total Scores and Overall Impact Question for Responders and Non-Responders | This outcome is a measure of sensitivity of the NI Diary to change in nocturia. The NI Diary is a 12-item instrument consisting of 11 core items and an overall impact question (Q12). The NI total score is defined as the sum of the 11 core items scores. The overall impact question (Q12) and the NI total score were transformed using Fisher's z transformation, i.e. the scores were based on a standardized scale from 0 (lowest impact) to 100 (highest impact). The difference in mean change in NI total score for subjects who experienced a reduction from baseline of <33% in nocturnal voids at the Month 1 visit (non-responders) versus those with a reduction in nocturnal voids from Baseline of ≥33% (responders) was estimated. | Day 1 (Baseline), Month 1 | 
| Cohen's D Effect Size in Responsiveness in the Nocturia Impact (NI) Total Scores and Overall Impact Question as Measured From Baseline (Day 1) to Month 1 | The responsiveness of the NI Diary was measured with Cohen's D effect size. The effect size was calculated for active treatment versus placebo, based on change from Baseline to Month 1. The effect size was evaluated as small, medium, or large if D was <=0.35, >0.35 - 0.65, or >0.65, respectively. Mean values are the Cohen's D effect size. Standard deviation is the pooled standard deviation. | Day 1 (Baseline), Month 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Internal Consistency of the Nocturia Impact (NI) Total Score for Each Day NI Diaries Were Completed Assessed as Cronbach's Alpha Values | Cronbach's alpha (CA) is a measure of the internal consistency of the Nocturia Impact (NI) Total scores. Higher scores indicate a more reliable (precise) instrument. A value of 0.70 set as the benchmark for declaring the scale as internally consistent. Cronbach's alpha was assessed for each of the three consecutive days NI diaries were completed during screening (Day -20 to Day -18), baseline (Day -2 to Day 1) and Month 1 (Day 28 to Day 30). | Screening (Day -20 to Day -18), Baseline (Day -2 to Day 1) and Treatment (Day 28 to Day 30) | 
| Construct Validity For the Nocturia Impact (NI) Total Scores and Overall Impact Question (Q12) for Participants With High/Low Number of Nocturnal Voids | The known group validity was assessed by comparing participants who experienced ≥3 nocturnal voids to those who experienced <3 nocturnal voids, using the average over 3 days for the Screening and Baseline diaries. Results are reported for the NI Total Scores and the Overall Impact Question (Q12). The NI Diary is a 12-item instrument consisting of 11 core items and an overall impact question (Q12). The NI total score is defined as the sum of the 11 core items scores. The overall impact question (Q12) and the NI total score were transformed using Fisher's z transformation, i.e. the scores were based on a standardized scale from 0 (lowest impact) to 100 (highest impact). | Screening (Day -20), Baseline (Day 1) | 
| Change From Baseline to Month 1 on Nocturia Impact (NI) Total Score | The NI Diary is a 12-item instrument consisting of 11 core items and an overall impact question (Q12). Responses are scored from 0 (no impact) to 4 (highest impact); the NI total score is the sum of the 11 core items scores (range of 0-44) which is then transformed to a 0-100 scale (high score indicates high impact). The NI total score was analyzable only if all 11 items (Q1-Q11) had non-missing responses. Otherwise, it was defined as missing. Missing values were not imputed. The average over the 3-day diary period prior to baseline (Day 1) and Month 1 was used for the overall impact score. Negative change from baseline scores indicate a decrease in impact caused by nocturia. | Baseline (Day -2 to Day 1), Treatment (Day 28-30) | 
| 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. 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 1 month | 
| 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 one day of the last dose of desmopressin. | Day 1 up to 1 month |