Nocturia
Conditions
Brief summary
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.
Interventions
DRUGDesmopressin
DRUGPlacebo
Sponsors
Ferring Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Mean Number of Nocturnal Voids Averaged Over a 3-Month Period | Day 1 (Baseline), Week 1, Months 1, 2, 3 (3-month double-blind treatment 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. |
| Adjusted Probability of Participants Achieving a >33% Reduction From Baseline in Number of Nocturnal Voids for All During-Treatment Visits up to Month 3 | Day 1 (Baseline), Week 1, Months 1, 2, 3 (3-month double-blind treatment period) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Adjusted Probability of Participants Achieving a >33% Reduction From Baseline in Number of Nocturnal Voids at Month 3 | Day 1 (Baseline), 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). |
| Change From Baseline in Nocturnal Urine Volume at Month 3 | Day 1 (Baseline), 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). |
| Change From Baseline in 24-Hour Urine Volume at Month 3 | Day 1 (Baseline), 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). |
| Change From Baseline in Mean Time to First Nocturnal Void at Month 3 | Day 1 (Baseline), 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). |
| Summary of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Open-Label Period | Month 1 of open-label period (Month 4 of treatment) | 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. |
| Minimum Post-Treatment Serum Sodium Levels in the Double-Blind Period | Day 1 through Month 3 (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. |
| Minimum Post-Treatment Serum Sodium Levels in the Open-Label Period | Month 1 of open-label period (Month 4 of treatment) | 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. |
| Summary of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Double-Blind Period | From Day 1 through Month 3 (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. |
| Change From Baseline in Mean Number of Nocturnal Voids at Month 3 | Day 1 (Baseline), 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). |
Countries
Canada, United States
Participant flow
Pre-assignment details
A total of 1013 participants were screened; 618 were screening failures and 395 were randomized. The most common reason for screening failure was non-fulfillment of inclusion/exclusion criteria (535 participants); 23 participants withdrew consent prior to randomization and 60 participants had other reasons for screening failure.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Double-Blind 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. | 142 |
| Desmopressin 50 μg Double-Blind 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. | 119 |
| Desmopressin 75 μg Double-Blind 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. | 124 |
| Total | 385 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| 1-Month Open-Label Extension Period | Adverse Event | 2 | 0 | 2 |
| 1-Month Open-Label Extension Period | Lost to Follow-up | 0 | 1 | 0 |
| 1-Month Open-Label Extension Period | Other Reason | 0 | 1 | 0 |
| 1-Month Open-Label Extension Period | Protocol Violation | 1 | 0 | 2 |
| 1-Month Open-Label Extension Period | Withdrawal by Subject | 1 | 1 | 1 |
| 3-Month Double-Blind Period | Adverse Event | 6 | 4 | 8 |
| 3-Month Double-Blind Period | Lost to Follow-up | 4 | 5 | 3 |
| 3-Month Double-Blind Period | Protocol Violation | 3 | 6 | 6 |
| 3-Month Double-Blind Period | Withdrawal by Subject | 6 | 8 | 9 |
Baseline characteristics
| Characteristic | Placebo Double-Blind | Desmopressin 50 μg Double-Blind | Desmopressin 75 μg Double-Blind | Total |
|---|---|---|---|---|
| Age, Continuous | 60.8 years STANDARD_DEVIATION 14.2 | 60.8 years STANDARD_DEVIATION 13.2 | 60.1 years STANDARD_DEVIATION 11.6 | 60.6 years STANDARD_DEVIATION 13.1 |
| Age, Customized <65 years | 74 participants | 62 participants | 64 participants | 200 participants |
| Age, Customized >=65 years | 68 participants | 57 participants | 60 participants | 185 participants |
| Body Mass Index (BMI) | 29.2 kg/m^2 STANDARD_DEVIATION 5.25 | 29.3 kg/m^2 STANDARD_DEVIATION 4.77 | 29.2 kg/m^2 STANDARD_DEVIATION 4.79 | 29.2 kg/m^2 STANDARD_DEVIATION 4.95 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 participants | 0 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Asian | 2 participants | 2 participants | 3 participants | 7 participants |
| Race/Ethnicity, Customized Black or African American | 27 participants | 18 participants | 22 participants | 67 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 20 participants | 25 participants | 29 participants | 74 participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 122 participants | 94 participants | 95 participants | 311 participants |
| Race/Ethnicity, Customized White | 112 participants | 99 participants | 99 participants | 310 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 142 Participants | 119 Participants | 124 Participants | 385 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 119 | 7 / 122 | 5 / 143 | 0 / 101 | 0 / 102 | 1 / 124 |
| serious Total, serious adverse events | 4 / 119 | 5 / 122 | 1 / 143 | 0 / 101 | 1 / 102 | 2 / 124 |
Outcome results
Primary
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.
Time frame: Day 1 (Baseline), Week 1, Months 1, 2, 3 (3-month double-blind treatment period)
Population: Full analysis set (FAS).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Desmopressin 75 μg Double-Blind | Adjusted Probability of Participants Achieving a >33% Reduction From Baseline in Number of Nocturnal Voids for All During-Treatment Visits up to Month 3 | 0.67 probability |
| Desmopressin 50 μg Double-Blind | Adjusted Probability of Participants Achieving a >33% Reduction From Baseline in Number of Nocturnal Voids for All During-Treatment Visits up to Month 3 | 0.67 probability |
| Placebo Double-Blind | Adjusted Probability of Participants Achieving a >33% Reduction From Baseline in Number of Nocturnal Voids for All During-Treatment Visits up to Month 3 | 0.50 probability |
Comparison: 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.p-value: 0.000495% CI: [1.38, 3.03]Generalized Estimating Equation (GEE)
Comparison: 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.p-value: 0.000995% CI: [1.32, 2.96]Generalized Estimating Equation (GEE)
Primary
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.
Time frame: Day 1 (Baseline), Week 1, Months 1, 2, 3 (3-month double-blind treatment period)
Population: Full analysis set (FAS).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Desmopressin 75 μg Double-Blind | Change From Baseline in Mean Number of Nocturnal Voids Averaged Over a 3-Month Period | Month 2 (n=113, 107, 132) | -1.43 nocturnal voids | Standard Deviation 1.04 |
| Desmopressin 75 μg Double-Blind | Change From Baseline in Mean Number of Nocturnal Voids Averaged Over a 3-Month Period | Week 1 (n=120, 116, 141) | -1.06 nocturnal voids | Standard Deviation 1.9 |
| Desmopressin 75 μg Double-Blind | Change From Baseline in Mean Number of Nocturnal Voids Averaged Over a 3-Month Period | Month 3 (n=106, 103, 125) | -1.37 nocturnal voids | Standard Deviation 1.13 |
| Desmopressin 75 μg Double-Blind | Change From Baseline in Mean Number of Nocturnal Voids Averaged Over a 3-Month Period | Month 1 (n=117, 112, 139) | -1.4 nocturnal voids | Standard Deviation 1.01 |
| Desmopressin 50 μg Double-Blind | Change From Baseline in Mean Number of Nocturnal Voids Averaged Over a 3-Month Period | Month 2 (n=113, 107, 132) | -1.4 nocturnal voids | Standard Deviation 1.04 |
| Desmopressin 50 μg Double-Blind | Change From Baseline in Mean Number of Nocturnal Voids Averaged Over a 3-Month Period | Month 1 (n=117, 112, 139) | -1.31 nocturnal voids | Standard Deviation 1.01 |
| Desmopressin 50 μg Double-Blind | Change From Baseline in Mean Number of Nocturnal Voids Averaged Over a 3-Month Period | Month 3 (n=106, 103, 125) | -1.25 nocturnal voids | Standard Deviation 1.01 |
| Desmopressin 50 μg Double-Blind | Change From Baseline in Mean Number of Nocturnal Voids Averaged Over a 3-Month Period | Week 1 (n=120, 116, 141) | -0.973 nocturnal voids | Standard Deviation 0.898 |
| Placebo Double-Blind | Change From Baseline in Mean Number of Nocturnal Voids Averaged Over a 3-Month Period | Month 3 (n=106, 103, 125) | -0.984 nocturnal voids | Standard Deviation 1.04 |
| Placebo Double-Blind | Change From Baseline in Mean Number of Nocturnal Voids Averaged Over a 3-Month Period | Week 1 (n=120, 116, 141) | -0.591 nocturnal voids | Standard Deviation 1.05 |
| Placebo Double-Blind | Change From Baseline in Mean Number of Nocturnal Voids Averaged Over a 3-Month Period | Month 1 (n=117, 112, 139) | -0.928 nocturnal voids | Standard Deviation 1.96 |
| Placebo Double-Blind | Change From Baseline in Mean Number of Nocturnal Voids Averaged Over a 3-Month Period | Month 2 (n=113, 107, 132) | -1.01 nocturnal voids | Standard Deviation 1.14 |
Comparison: 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.~A summary of mean change in nocturnal voids, assessed longitudinally during 3 months of treatment, is presented below for the FAS using LOCF.p-value: <0.000195% CI: [-0.61, -0.22]ANCOVA
Comparison: 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.~A summary of mean change in nocturnal voids, assessed longitudinally during 3 months of treatment, is presented below for the FAS using LOCF.p-value: 0.000395% CI: [-0.57, -0.17]ANCOVA
Secondary
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).
Time frame: Day 1 (Baseline), Month 3
Population: FAS, including participants with complete data supporting this outcome in the participant diary.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Desmopressin 75 μg Double-Blind | Adjusted Probability of Participants Achieving a >33% Reduction From Baseline in Number of Nocturnal Voids at Month 3 | 0.68 probability |
| Desmopressin 50 μg Double-Blind | Adjusted Probability of Participants Achieving a >33% Reduction From Baseline in Number of Nocturnal Voids at Month 3 | 0.66 probability |
| Placebo Double-Blind | Adjusted Probability of Participants Achieving a >33% Reduction From Baseline in Number of Nocturnal Voids at Month 3 | 0.54 probability |
Comparison: The active treatment groups were compared to placebo using a step-down approach from highest dose (75 µg) to lowest dose (50 µg).p-value: 0.023395% CI: [1.08, 3.02]Regression, Logistic
Comparison: The active treatment groups were compared to placebo using a step-down approach from highest dose (75 µg) to lowest dose (50 µg).p-value: 0.038695% CI: [1.03, 2.87]Regression, Logistic
Secondary
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).
Time frame: Day 1 (Baseline), Month 3
Population: FAS, including participants with complete data supporting this outcome in the participant diary.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Desmopressin 75 μg Double-Blind | Change From Baseline in 24-Hour Urine Volume at Month 3 | -224 mL | Standard Deviation 549 |
| Desmopressin 50 μg Double-Blind | Change From Baseline in 24-Hour Urine Volume at Month 3 | -194 mL | Standard Deviation 491 |
| Placebo Double-Blind | Change From Baseline in 24-Hour Urine Volume at Month 3 | -197 mL | Standard Deviation 442 |
Comparison: The active treatment groups were compared to placebo using a step-down approach from highest dose (75 µg) to lowest dose (50 µg).p-value: 0.412695% CI: [-153.94, 63.32]ANCOVA
Comparison: The active treatment groups were compared to placebo using a step-down approach from highest dose (75 µg) to lowest dose (50 µg).p-value: 0.735395% CI: [-127.99, 90.41]ANCOVA
Secondary
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).
Time frame: Day 1 (Baseline), Month 3
Population: Full Analysis Set (FAS), including participants with complete data supporting this outcome in the participant diary.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Desmopressin 75 μg Double-Blind | Change From Baseline in Mean Number of Nocturnal Voids at Month 3 | -1.37 nocturnal voids | Standard Deviation 1.13 |
| Desmopressin 50 μg Double-Blind | Change From Baseline in Mean Number of Nocturnal Voids at Month 3 | -1.25 nocturnal voids | Standard Deviation 1.01 |
| Placebo Double-Blind | Change From Baseline in Mean Number of Nocturnal Voids at Month 3 | -0.984 nocturnal voids | Standard Deviation 1.04 |
Comparison: Change from baseline in the adjusted mean number of nocturnal voids in the FAS using LOCF.~The active treatment groups were compared to placebo using a step-down approach from highest dose (75 µg) to lowest dose (50 µg).p-value: 0.002995% CI: [-0.57, -0.12]ANCOVA
Comparison: Change from baseline in the adjusted mean number of nocturnal voids in the FAS using LOCF.~The active treatment groups were compared to placebo using a step-down approach from highest dose (75 µg) to lowest dose (50 µg).p-value: 0.012895% CI: [-0.52, -0.06]ANCOVA
Secondary
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).
Time frame: Day 1 (Baseline), Month 3
Population: FAS, including participants with complete data supporting this outcome in the participant diary.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Desmopressin 75 μg Double-Blind | Change From Baseline in Mean Time to First Nocturnal Void at Month 3 | 117 minutes | Standard Deviation 130 |
| Desmopressin 50 μg Double-Blind | Change From Baseline in Mean Time to First Nocturnal Void at Month 3 | 113 minutes | Standard Deviation 119 |
| Placebo Double-Blind | Change From Baseline in Mean Time to First Nocturnal Void at Month 3 | 71.5 minutes | Standard Deviation 108 |
Comparison: The active treatment groups were compared to placebo using a step-down approach from highest dose (75 µg) to lowest dose (50 µg).p-value: 0.002695% CI: [15.02, 70.51]ANCOVA
Comparison: The active treatment groups were compared to placebo using a step-down approach from highest dose (75 µg) to lowest dose (50 µg).p-value: 0.006495% CI: [11.03, 66.88]ANCOVA
Secondary
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).
Time frame: Day 1 (Baseline), Month 3
Population: FAS, including participants with complete data supporting this outcome in the participant diary.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Desmopressin 75 μg Double-Blind | Change From Baseline in Nocturnal Urine Volume at Month 3 | -199 mL | Standard Deviation 274 |
| Desmopressin 50 μg Double-Blind | Change From Baseline in Nocturnal Urine Volume at Month 3 | -186 mL | Standard Deviation 263 |
| Placebo Double-Blind | Change From Baseline in Nocturnal Urine Volume at Month 3 | -144 mL | Standard Deviation 260 |
Comparison: The active treatment groups were compared to placebo using a step-down approach from highest dose (75 µg) to lowest dose (50 µg).p-value: 0.003495% CI: [-143.69, -28.64]ANCOVA
Comparison: The active treatment groups were compared to placebo using a step-down approach from highest dose (75 µg) to lowest dose (50 µg).p-value: 0.008695% CI: [-135.7, -19.89]ANCOVA
Secondary
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.
Time frame: Day 1 through Month 3 (double-blind period)
Population: Safety analysis set (SAS)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Desmopressin 75 μg Double-Blind | Minimum Post-Treatment Serum Sodium Levels in the Double-Blind Period | 130-134 mmol/L | 2 participants |
| Desmopressin 75 μg Double-Blind | Minimum Post-Treatment Serum Sodium Levels in the Double-Blind Period | ≤125 mmol/L | 0 participants |
| Desmopressin 75 μg Double-Blind | Minimum Post-Treatment Serum Sodium Levels in the Double-Blind Period | ≥135 mmol/L | 141 participants |
| Desmopressin 75 μg Double-Blind | Minimum Post-Treatment Serum Sodium Levels in the Double-Blind Period | 126-129 mmol/L | 0 participants |
| Desmopressin 50 μg Double-Blind | Minimum Post-Treatment Serum Sodium Levels in the Double-Blind Period | 130-134 mmol/L | 9 participants |
| Desmopressin 50 μg Double-Blind | Minimum Post-Treatment Serum Sodium Levels in the Double-Blind Period | 126-129 mmol/L | 0 participants |
| Desmopressin 50 μg Double-Blind | Minimum Post-Treatment Serum Sodium Levels in the Double-Blind Period | ≤125 mmol/L | 2 participants |
| Desmopressin 50 μg Double-Blind | Minimum Post-Treatment Serum Sodium Levels in the Double-Blind Period | ≥135 mmol/L | 108 participants |
| Placebo Double-Blind | Minimum Post-Treatment Serum Sodium Levels in the Double-Blind Period | 126-129 mmol/L | 5 participants |
| Placebo Double-Blind | Minimum Post-Treatment Serum Sodium Levels in the Double-Blind Period | ≤125 mmol/L | 4 participants |
| Placebo Double-Blind | Minimum Post-Treatment Serum Sodium Levels in the Double-Blind Period | ≥135 mmol/L | 101 participants |
| Placebo Double-Blind | Minimum Post-Treatment Serum Sodium Levels in the Double-Blind Period | 130-134 mmol/L | 12 participants |
Secondary
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.
Time frame: Month 1 of open-label period (Month 4 of treatment)
Population: Safety analysis set (SAS) during open-label treatment period
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Desmopressin 75 μg Double-Blind | Minimum Post-Treatment Serum Sodium Levels in the Open-Label Period | ≤125 mmol/L | 1 participants |
| Desmopressin 75 μg Double-Blind | Minimum Post-Treatment Serum Sodium Levels in the Open-Label Period | ≥135 mmol/L | 110 participants |
| Desmopressin 75 μg Double-Blind | Minimum Post-Treatment Serum Sodium Levels in the Open-Label Period | 130-134 mmol/L | 10 participants |
| Desmopressin 75 μg Double-Blind | Minimum Post-Treatment Serum Sodium Levels in the Open-Label Period | 126-129 mmol/L | 3 participants |
| Desmopressin 50 μg Double-Blind | Minimum Post-Treatment Serum Sodium Levels in the Open-Label Period | 126-129 mmol/L | 1 participants |
| Desmopressin 50 μg Double-Blind | Minimum Post-Treatment Serum Sodium Levels in the Open-Label Period | 130-134 mmol/L | 12 participants |
| Desmopressin 50 μg Double-Blind | Minimum Post-Treatment Serum Sodium Levels in the Open-Label Period | ≥135 mmol/L | 88 participants |
| Desmopressin 50 μg Double-Blind | Minimum Post-Treatment Serum Sodium Levels in the Open-Label Period | ≤125 mmol/L | 0 participants |
| Placebo Double-Blind | Minimum Post-Treatment Serum Sodium Levels in the Open-Label Period | ≥135 mmol/L | 89 participants |
| Placebo Double-Blind | Minimum Post-Treatment Serum Sodium Levels in the Open-Label Period | ≤125 mmol/L | 1 participants |
| Placebo Double-Blind | Minimum Post-Treatment Serum Sodium Levels in the Open-Label Period | 130-134 mmol/L | 11 participants |
| Placebo Double-Blind | Minimum Post-Treatment Serum Sodium Levels in the Open-Label Period | 126-129 mmol/L | 1 participants |
Secondary
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.
Time frame: From Day 1 through Month 3 (double-blind period)
Population: Safety analysis set (SAS)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Desmopressin 75 μg Double-Blind | Summary of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Double-Blind Period | Severe AEs | 2 participants |
| Desmopressin 75 μg Double-Blind | Summary of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Double-Blind Period | ADRs leading to discontinuation | 4 participants |
| Desmopressin 75 μg Double-Blind | Summary of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Double-Blind Period | AEs leading to discontinuation | 7 participants |
| Desmopressin 75 μg Double-Blind | Summary of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Double-Blind Period | All AEs | 58 participants |
| Desmopressin 75 μg Double-Blind | Summary of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Double-Blind Period | Deaths | 0 participants |
| Desmopressin 75 μg Double-Blind | Summary of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Double-Blind Period | Serious AEs (SAEs) | 1 participants |
| Desmopressin 75 μg Double-Blind | Summary of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Double-Blind Period | Adverse drug reactions (ADRs) | 22 participants |
| Desmopressin 50 μg Double-Blind | Summary of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Double-Blind Period | AEs leading to discontinuation | 4 participants |
| Desmopressin 50 μg Double-Blind | Summary of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Double-Blind Period | All AEs | 46 participants |
| Desmopressin 50 μg Double-Blind | Summary of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Double-Blind Period | Severe AEs | 2 participants |
| Desmopressin 50 μg Double-Blind | Summary of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Double-Blind Period | Adverse drug reactions (ADRs) | 23 participants |
| Desmopressin 50 μg Double-Blind | Summary of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Double-Blind Period | ADRs leading to discontinuation | 4 participants |
| Desmopressin 50 μg Double-Blind | Summary of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Double-Blind Period | Serious AEs (SAEs) | 4 participants |
| Desmopressin 50 μg Double-Blind | Summary of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Double-Blind Period | Deaths | 0 participants |
| Placebo Double-Blind | Summary of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Double-Blind Period | ADRs leading to discontinuation | 5 participants |
| Placebo Double-Blind | Summary of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Double-Blind Period | Severe AEs | 2 participants |
| Placebo Double-Blind | Summary of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Double-Blind Period | Deaths | 0 participants |
| Placebo Double-Blind | Summary of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Double-Blind Period | Serious AEs (SAEs) | 5 participants |
| Placebo Double-Blind | Summary of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Double-Blind Period | AEs leading to discontinuation | 7 participants |
| Placebo Double-Blind | Summary of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Double-Blind Period | Adverse drug reactions (ADRs) | 20 participants |
| Placebo Double-Blind | Summary of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Double-Blind Period | All AEs | 49 participants |
Secondary
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.
Time frame: Month 1 of open-label period (Month 4 of treatment)
Population: Safety analysis set (SAS) for open label-treatment period
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Desmopressin 75 μg Double-Blind | Summary of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Open-Label Period | AEs leading to discontinuation | 2 participants |
| Desmopressin 75 μg Double-Blind | Summary of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Open-Label Period | Severe AEs | 0 participants |
| Desmopressin 75 μg Double-Blind | Summary of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Open-Label Period | Serious AEs (SAEs) | 2 participants |
| Desmopressin 75 μg Double-Blind | Summary of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Open-Label Period | Adverse drug reactions (ADRs) | 9 participants |
| Desmopressin 75 μg Double-Blind | Summary of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Open-Label Period | ADRs leading to discontinuation | 2 participants |
| Desmopressin 75 μg Double-Blind | Summary of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Open-Label Period | All AEs | 26 participants |
| Desmopressin 75 μg Double-Blind | Summary of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Open-Label Period | Deaths | 0 participants |
| Desmopressin 50 μg Double-Blind | Summary of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Open-Label Period | Serious AEs (SAEs) | 0 participants |
| Desmopressin 50 μg Double-Blind | Summary of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Open-Label Period | Deaths | 0 participants |
| Desmopressin 50 μg Double-Blind | Summary of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Open-Label Period | All AEs | 23 participants |
| Desmopressin 50 μg Double-Blind | Summary of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Open-Label Period | Severe AEs | 0 participants |
| Desmopressin 50 μg Double-Blind | Summary of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Open-Label Period | Adverse drug reactions (ADRs) | 6 participants |
| Desmopressin 50 μg Double-Blind | Summary of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Open-Label Period | AEs leading to discontinuation | 0 participants |
| Desmopressin 50 μg Double-Blind | Summary of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Open-Label Period | ADRs leading to discontinuation | 0 participants |
| Placebo Double-Blind | Summary of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Open-Label Period | All AEs | 23 participants |
| Placebo Double-Blind | Summary of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Open-Label Period | ADRs leading to discontinuation | 2 participants |
| Placebo Double-Blind | Summary of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Open-Label Period | AEs leading to discontinuation | 2 participants |
| Placebo Double-Blind | Summary of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Open-Label Period | Deaths | 0 participants |
| Placebo Double-Blind | Summary of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Open-Label Period | Severe AEs | 1 participants |
| Placebo Double-Blind | Summary of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Open-Label Period | Serious AEs (SAEs) | 1 participants |
| Placebo Double-Blind | Summary of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Open-Label Period | Adverse drug reactions (ADRs) | 9 participants |